A 5-Week-Old Boy with Failure to Thrive, Marked Hyperkalemia, and Hyponatremia

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1 Clinical Chemistry 62: (2016) Clinical Case Study A 5-Week-Old Boy with Failure to Thrive, Marked Hyperkalemia, and Hyponatremia Min Xu, 1,2* Carolina Di Blasi, 3,4 Jane Dickerson, 1,2 Rhona Jack, 1,2 and Joe C. Rutledge 1,2 CASE DESCRIPTION A 5-week-old white boy presented to the emergency department after referral from his primary care physician with concerns for failure to thrive. The patient s birth weight was 2892 g at 37 weeks of gestation (10th percentile). He was 2665 g at 5 weeks of age ( second percentile). He had been exclusively breastfed for the first 3 weeks of his life. At 3 weeks of age, he was introduced to a bottle with expressed breast milk but showed little interest in the bottle. At a well-child checkup at 4 weeks of age, his weight was down, and formula supplementation was recommended. In the last 3 days before the, he had been lethargic and had difficulty feeding. He had 2 episodes of projectile vomiting during that week. There was a noticeable reduction in the amount of stool and urine output during the last 2 days before, without fever or diarrhea. The patient was born at 37 weeks of gestation by spontaneous vaginal delivery. Mother was found to be group B Streptococcus (GBS) 5 positive but was not treated before delivery, so the patient was monitored for 48 h in the hospital before being discharged home. Mother also had a history of bilateral vesicoureteral reflux and reimplantation surgery. There was no other history of genital, urinary, or kidney abnormalities. On exam, the patient was cachectic and lethargic but did have warm extremities, brisk capillary refill ( 2 s), and good distal pulses. No skin hyperpigmentation was seen and the genitalia were normal. Laboratory tests were significant for potassium 10.2 mmol/l, sodium 116 mmol/l, chloride 91 mmol/l, blood urea nitrogen (BUN)64 mg/dl (22.9 mmol/l), creatinine 0.7 mg/dl (61.9 mol/l), glucose 88 mg/dl (4.9 mmol/l), ph 1 Department of Laboratories, Seattle Children s Hospital, Seattle, WA; 2 Department of Laboratory Medicine, University of Washington, Seattle, WA; 3 Department of Endocrinology,SeattleChildren shospital,seattle,wa; 4 DepartmentofPediatrics,Universityof Washington, Seattle, WA. * Address correspondence to this author at: Department of Laboratories, OC.8.731, Seattle Children s Hospital, 4800 Sand Point Way NE, Seattle, WA Fax ; min.xu@seattlechildrens.org. Received December 10, 2015; accepted February 11, DOI: /clinchem American Association for Clinical Chemistry 5 Nonstandard abbreviations: GBS, group B Streptococcus; BUN, blood urea nitrogen; CAH, congenital adrenal hyperplasia; ACTH, adrenocorticotropic hormone; 17-OHP, 17- hydroxyprogesterone; UTI, urinary tract infection; PHA, pseudohypoaldosteronism; WNK, with-no-lysine kinase; IAP, intrapartum antimicrobial prophylaxis. 7.29, CO 2 pressure (PCO 2 ) 29 mmhg, and total CO mmol/l (Table 1). The specimen was not hemolyzed. Contamination of the sample with potassium was originally suspected by the medical technologist. Communication with clinical staff confirmed the quality of the sample. Electrocardiogram showed no electrolyterelated changes. The patient s blood pressure was 75/41 mmhg (normal interval 65 85/45 55 mmhg). The patient received normal saline boluses to supplement sodium, kayexalate to chelate potassium, and calcium gluconate to antagonize the membrane actions of hyperkalemia. Although he had 2 normal newborn screens, the possibility of congenital adrenal hyperplasia (CAH) was still in the differential diagnoses owing to such high potassium and low sodium. The patient was started on stress-dose steroids after measurement of baseline adrenocorticotropic hormone (ACTH), renin, aldosterone, 17-hydroxyprogesterone (17-OHP), and cortisol. Urinalysis for the possibility of urinary tract infection (UTI) was also performed. One hour later, sodium increased to 125 mmol/l and potassium decreased to 7.9 mmol/l. The patient was admitted to the neonatal intensive care unit for further evaluation and management. CASE RESOLUTION QUESTIONS TO CONSIDER 1. What is the differential diagnosis of a patient with marked hyperkalemia, hyponatremia, and metabolic acidosis? 2. What are the diagnostic tests for CAH? 3. What are the consequences of neonatal infection of GBS? On the second day of, cortisol was increased at 38.3 g/dl (1057 nmol/l), and 17-OHP was 29 ng/dl (0.88 nmol/l) (Table 1). ACTH, renin, and aldosterone were not tested due to lack of adequate sample volume. Urinalysis on the first day of showed specific gravity 1.007, ph 5.5, urine leukocyte esterase 3, urine nitrite negative, protein 1, glucose negative, ketones negative, urobilinogen 0.2 mg/dl, bilirubin negative, occult blood 3, white blood cell count 100/ high power field, bacteria moderate, red blood cell negative, a few amorphous crystals, and a few white blood 1439

2 Table 1. Relevant laboratory results during inpatient period. Test At 1 h after 4 h after 20 h after Day of discharge, 1 week after Reference interval Sodium, mmol/l 119 C a 125 L 125 L Potassium, mmol/l 10.2 C 7.9 C 6.8 C Chloride, mmol/l 93 L Carbon dioxide, mmol/l 15 L 12 L 13 L Anion gap, mmol/l b Glucose, mg/dl 88 (4.9 mmol/l) 71 (3.9 mmol/l) 68 (3.8 mmol/l) 89 (4.9 mmol/l) ( mmol/l) BUN, mg/dl 64 H (22.9 mmol/l) 49 H (17.5 mmol/l) 24 H (8.6 mmol/l) <4 L (<1.4 mmol/l) 6 20 ( mmol/l) Creatinine, mg/dl 0.7 H (61.9 μmol/l) 0.6 (53.1 μmol/l) 0.4 (35.4 μmol/l) 0.4 (35.4 μmol/l) ( μmol/l) ph 7.29 L PCO 2, venous, mmhg 29 L Cortisol, random, μg/dl 38.3 H (1057 nmol/l) ( nmol/l) 17-OHP, ng/dl 29 (0.88 nmol/l) ( nmol/l) a Flags: C, critical; L, low; H, high. b Calculated as (sodium and potassium) (chloride and CO2 ) Clinical Chemistry 62:11 (2016)

3 cell clumps. Owing to the abnormal urinalysis suspicious for UTI, renal ultrasound was performed that showed bilateral moderate to severe hydronephrosis. There was bilateral proximal and distal ureteral dilation. Voiding cystourethrogram showed bilateral severe (grade 5) vesicoureteral reflux with normal urethra. Bilateral kidneys were normal in size. On the third day of the, urine culture showed cfu/ml Streptococcus agalactiae (Group B). Both blood and cerebrospinal fluid cultures were negative. The patient was treated for acute pyelonephritis with intravenous ampicillin. Although aldosterone could not be tested before treatment with hydrocortisone owing to inadequate sample, the adequate cortisol and normal 17-OHP essentially ruled out the diagnosis of CAH from 21-hydroxylase deficiency or primary adrenal insufficiency as the cause of the patient s electrolyte disarrangements. The electrolyte abnormality appeared secondary to mineralocorticoid deficiency or resistance. The combination of positive GBS in the urine and abnormal renal ultrasound supported a renal cause of the patient s hypoaldosteronism or pseudohypoaldosteronism as the diagnosis. The hydrocortisone was discontinued on the third day of. The patient s electrolyte disturbances were corrected quickly with antibiotic treatment and rehydration (Table 1). He continued to do well off hydrocortisone with no hypotension or signs of hypoglycemia. The patient was treated with intravenous ampicillin for 7 days and transitioned to oral amoxicillin. He was discharged on the eighth day of the with prescribed oral amoxicillin for another 7 days. The follow-up clinic visits at 1 and 4 months after discharge showed normal electrolytes. DISCUSSION Aldosterone is a mineralocorticoid hormone synthesized by the zona glomerulosa of the adrenal cortex. The production of aldosterone is under the regulation of the renin-angiotensin system and potassium ion. The function of aldosterone in humans is to increase sodium reabsorption from the distal convoluted tubules of kidneys as well as in cells of other tissues involved with conservation of salt, such as the colon, sweat glands, and salivary glands. Water and chloride are reabsorbed and potassium is excreted, while Na and H ions are exchanged across the proximal tubule. Potassium ions compete for hydrogen ions in the Na H exchange, so if there is an increase in potassium, urine will not be acidified, and hypochloremic (nonanion gap) metabolic acidosis results. Hypoaldosteronism, therefore, will result in hyponatremia, hypochloremia, hyperkalemia, metabolic acidosis, and dehydration. The major causes of hypoaldosteronism are either reduced aldosterone production (primary) or aldosterone resistance (secondary). Primary hypoaldosteronism is caused by dysfunction of the reninangiotensin pathway, loss of enzyme activity for the synthesis of aldosterone, or situations that cause adrenal cortex damage. Secondary hypoaldosteronism, also called pseudohypoaldosteronism (PHA) is characterized by increased aldosterone concentrations but functional aldosterone deficiency. Possible causes of PHA include mineralocorticoid receptor defects, or dysfunction of renal tubules in response to aldosterone stimulation. For infants, the major cause of hypoaldosteronism is CAH with an incidence of approximately 1/ This is an autosomal-recessive genetic disorder with the vast majority (approximately 90%) caused by mutations in the CYP21A2 6 (cytochrome P450 family 21 subfamily A member 2) gene (OMIM#613815), resulting in the loss of 21-hydroxylase activity (1). Currently, newborn screening for CAH is mandated in all states in the US. The newborn screen for CAH in some states includes testing for 17-OHP within the first 72 h of birth, with repeat between 8 and 14 days of age (2). Symptoms of CAH vary depending on the type of the disease and time of diagnosis. Children with a mild form (nonclassic form) may not present with symptoms until adolescence. In children with severe CAH, symptoms usually develop within a few weeks after birth, presenting with poor feeding, vomiting, failure to thrive, electrolyte imbalance, dehydration, hypoglycemia, and metabolic acidosis. These symptoms result from severe aldosterone deficiency in the neonates, with salt-wasting crisis. These patients are also glucocorticoid deficient. The marked electrolyte imbalance in this patient raised the possibility of CAH. Although the patient had normal newborn screening results for CAH, the severity of the patient s salt wasting warranted the emergency steroid administration because of possible false-negative newborn screening. False-negative newborn screen for CAH occurs at a rate of 20% 30% (3). PHA is a rare heterogeneous syndrome characterized by functional hypoaldosteronism with normal or increased aldosterone concentration (4). It is caused by inability of distal convoluted tubules of the nephron to regulate electrolyte balance owing to mutations, infections, or other causes. The symptoms usually start in the neonatal period or early infancy and consist of salt wasting, hyperkalemia, metabolic acidosis, dehydration, and failure to thrive. Table 2 summarizes the different types of PHA (5 9). All patients with type 3 PHA have abnormal urinary tract anatomy and/or bacterial UTI (8, 9). In our patient, although the aldosterone were not measured because of lack of adequate sample, 6 Human Genes: CYP21A2, cytochrome P450 family 21 subfamily A member 2; NR3C2, nuclear receptor subfamily 3 group C member 2; SCNN1A, sodium channel epithelial 1 alpha subunit; SCNN1B, sodium channel epithelial 1 alphabeta subunit; SCNN1G, sodium channel epithelial 1 gamma subunit; WNK4, WNK lysine deficient protein kinase 4. Clinical Chemistry 62:11 (2016) 1441

4 POINTS TO REMEMBER Table 2. Summary of PHA. PHA Clinical presentation Aldosterone Etiology Treatment Sodium supplementation, improve with age Mutations in mineralocorticoid receptor gene NR3C2 at 4q31.1 Increased aldosterone Varies from asymptomatic to saltwasting, hyperkalemia, metabolic acidosis, dehydration Type 1 (autosomal dominant, renal form) [Geller et al. (5)] Rehydration, sodium supplementation and potassium chelating Mutations in epithelial sodium channel subunit genes SCNN1A (12p13.31), SCNN1B and SCNN1G (16p12.2) Increased aldosterone Presents early with severe dehydration, salt-wasting, hyperkalemia, metabolic acidosis, even cardiovascular collapse Type 1 (autosomal recessive, generalized form) [Chang et al. (6)] Chronic low-salt diet, thiazide-type diuretics Mutations in WNK4 (17q21.31), WNK1 (12p13.33) Normal or low aldosterone, low renin Salt retention, hyperkalemia, metabolic acidosis in infancy, hypertension 2 4 decades later Type 2 (also known as Gordon syndrome, familial hyperkalemia and hypertension, and chloride shunt syndrome) (autosomal dominant or sporadic) [Pathare et al. (7)] UTI, obstructive uropathy Antibiotics, correction of underlying uropathy Normal aldosterone Failure to thrive, salt-wasting, hyperkalemia, metabolic acidosis, dehydration Type 3 (transient, secondary) [Torun- Bayram et al. (8); Nandagopal (9)] The differential diagnosis of failure to thrive and saltwasting crisis of an infant should include CAH, hypoaldosteronism, and PHA. Even with the nationwide implementation of newborn screening for CAH, screening assays can yield both false negatives and false positives, and a normal newborn screen is not considered a definite rule-out. The best diagnostic tests for CAH are serum 17-OHP and cortisol. In the setting of low sodium and high potassium in a dehydrated infant, a serum aldosterone should be obtained in addition to screening for CAH. Pregnant women with GBS should be treated appropriately to prevent neonatal GBS infection. UTI and/or urinary tract malformation in an infant could result in transient PHA, which could cause a salt-wasting crisis. Recognizing this life-threatening situation is critical to institute proper treatment and prevent fatal consequences. The electrolyte abnormalities of this case, hyponatremia and hyperkalemia in a neonate, should make one consider doing a urinalysis to assess for UTI. the combination of failure to thrive, marked electrolyte imbalance at presentation, urinary tract anomaly with infection due to GBS, normalization of electrolytes with fluids and antibiotic treatment, slightly high cortisol concentration and multiple normal 17-OHP measurements, and persistent electrolyte normalization after discharge, is consistent with PHA type 3 caused by UTI and/or malformation. Neonates born from mothers with GBS colonization are at risk of developing serious invasive disease (meningitis, pneumonia, or sepsis). However, only 1% 2% will develop serious diseases (10). Intrapartum antimicrobial prophylaxis (IAP) for women with GBS has reduced the early onset ( 1 weeks of age) of neonatal infection. The common antibiotic agents include penicillin, ampicillin, or cefazolin (10). For our patient, IAP was not administered because of a rapid delivery. The patient was observed in the hospital for 2 days without signs of infection. However, he later developed UTI, likely due to congenital urinary tract anomaly and GBS colonization. The mechanism of PHA type 3 or secondary PHA type 1 caused by UTI and anomaly is still not known. It was hypothesized that aldosterone resistance of renal tubular cells might be the mechanism. Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or 1442 Clinical Chemistry 62:11 (2016)

5 analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article. References Authors Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest. 1. Turcu AF, Auchus RJ. Adrenal steroidogenesis and congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 2015;44: Chan CL, McFann K, Taylor L, Wright D, Zeitler PS, Barker JM. Congenital adrenal hyperplasia and the second newborn screen. J Pediatr 2013;163: Sarafoglou K, Banks K, Kyllo J, Pittock S, Thomas W. Cases of congenital adrenal hyperplasia missed by newborn screening in Minnesota. JAMA 2012;307: Riepe FG. Pseudohypoaldosteronism. Endocr Dev 2013;24: Geller DS, Rodriguez-Soriano J, Vallo Boado A, Schifter S, Bayer M, Chang SS, Lifton RP. Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type I. Nat Genet 1998;19: Chang SS, Grunder S, Hanukoglu A, Rösler A, Mathew PM, Hanukoglu I, et al. Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1. Nat Genet 1996;12: Pathare G, Hoenderop JG, Bindels RJ, San-Cristobal P. A molecularupdateonpseudohypoaldosteronismtypeii. Am J Physiol Renal Physiol 2013;305:F Torun-Bayram M, Soylu A, Kasap-Demir B, Alaygut D, Türkmen M, Kavukçu S. Secondary pseudohypoaldosteronism caused by urinary tract infection associated with urinary tract anomalies: case reports. Turk J Pediatr 2012;54(1): Nandagopal R, Vaidyanathan P, Kaplowitz P. Transient pseudohypoaldosteronism due to urinary tract infection in infancy: a report of 4 cases. Int J Pediatr Endocrinol 2009: Shane AL, Stoll BJ. Neonatal sepsis: progress towards improved outcomes. J Infect 2014;68(Suppl 1):S Commentary Dennis J. Dietzen * Neonatology notes typically begin with a litany of facts cloaked in abbreviations. A typical case description might go something like this: Boy Smith is a 1900-g, 40-cm infant born via spontaneous vaginal delivery at 35 weeks gestation to a 32-year-old, G4, P3, now 4 mother. Apgar scores were 8 and 9 at 1 and 5 min. Maternal serologies: O ; RPR (rapid plasma reagin) nonreactive; GC [(gonococcus)-chlamydia negative] negative; GBS (group B Streptococcus) unknown; and VZV (varicella zoster virus), hepatitis B and rubella immune; HIV, CMV (cytomegalovirus), and Toxo (toxoplasmosis) negative. You caught the GBS reference, right? It is not difficult to get desensitized to this barrage of information. To make matters worse, only about 1000 babies per year in the US experience disease as a result of maternal GBS infection. Severe complications from congenital GBS infection include sepsis, meningitis, and pneumonia. UTIs are very uncommon. GBS infection, therefore, is not typically near the top of the list of potential diagnoses in neonates with electrolyte disturbances. Washington University School of Medicine, St. Louis, MO. * Address correspondence to the author at: Washington University School of Medicine, Box 8116 One Childrens Place, Rm. 2N68, St. Louis, MO, Fax ; dietzen_d@kids.wustl.edu. Received March 29, 2016; accepted March 31, DOI: /clinchem American Association for Clinical Chemistry By contrast, CAH is near the top of the list because it is relatively common (approximately 1:15000 US births), and it requires urgent attention. Approximately 70% of CAH cases present with the possibility of a lifethreatening salt-wasting crisis. Diagnosis ought to be relatively straightforward even in the absence of aldosterone measurement because nearly all babies in the US are screened for CAH. Screening by measurement of 17-OH progesterone in newborns is far from perfect, however. For every 10 cases of authentic CAH detected by newborn screening, unaffected infants (many premature or low birthweight) may have increased 17-OH progesterone and another 1 2 affected infants will be missed. This case emphasizes yet again that proper clinical management depends upon careful correlation of history and physical findings to available biochemical data, particularly in pediatrics, where specimen scarcity often limits comprehensive laboratory testing. Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article. Authors Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest. Clinical Chemistry 62:11 (2016) 1443