CAPÍTULO 2: CONDUCTA ANTISOCIAL: TEORÍAS EXPLICATIVAS
III. MARCO EMPÍRICO
5. DISCUSIÓN Y CONCLUSIONES
5.2 Frente a los resultados encontrados
Hyperthyroidism Familial tumoral calcinosis Hyperostosis
Symptoms 0
Divalent ion metabolism
C.B. Langman · G. Ariceta · B. Hoppe
Hyperphosphatemia99
Divalent ion metabolism
C.B. Langman · G. Ariceta · B. Hoppe
Hyperphosphatemia1 – Normal serum P level varies with age, so that the defi nition of hyperphosphatemia is age dependent.
Normal P levels according to age are: neonates mean 6.5 mg/dl, range 4.8–7.4; infants 4.5–5.8 mg/dl (mean 5.0), mid-childhood 3.5–5.5 mg/dl (mean 4.4 mg/dl) and by late adolescence, values are similar to those in adults: range 2.4–4.5 mg/dl.
2 – Hyperphosphatemia is often asymptomatic.
An acute elevation in serum P level may acutely re-duce serum Ca levels with resultant symptoms of hy-pocalcemia including: paresthesias, tetany, seizures, psychological disturbances, cardiac arrhythmias, hy-potension and death. During chronic hyperphosphate-mia, serum Ca is usually normal or elevated and symp-toms are secondary to increased [P] × [Ca] product and include progressive metastatic tissue calcifi cation or, less often, acute calciphylaxis syndrome (rapid subcu-taneous and small vessels calcifi cation leading to pain-ful necrosis of skin and subcutaneous fat).
3 – With a normal dietary intake of P, 15–20% of the fi ltered P is excreted in the urine. There is a maxi-mum capacity of P reabsorption (TmpPO4) that varies with the GFR. During the fi rst 3 years of life, there is relative renal P retention which constitutes an appro-priate physiological adaptation to the demands for P during somatic growth. Interestingly, the adolescent growth spurt is not associated with P retention by the kidney.
4 – By far the most common cause of hyperphos-phatemia is acute or chronic renal failure. Hyperphos-phatemia usually occurs when GFR is less than 30% of normal, and although there is a low fractional reab-sorption of P in the remaining functional nephrons, absolute excretion falls. In acute renal failure, hyper-phosphatemia is usually observed during the oliguric phase.
Acute hyperphosphatemia occurs during the rapid breakdown of cells with release of intracellular P, such as in tumor-lysis syndrome, rhabdomyolysis, or se-vere hemolytic anemias. The levels of other intracel-lular cations such as potassium (K) and magnesium (Mg) are usually increased during these cytolytic pro-cesses.
5 – Mild hyperphosphatemia is typical of acro-megaly (growth hormone excess) and can be also de-tected in thyrotoxicosis, as both growth hormone and thyroxine increase the tubular reabsorption of P. Famil-ial tumoral calcinosis is a rare hereditary disorder of mineral metabolism characterized by increased proxi-mal tubular reabsorption rate of P and increased levels of 1,25(OH)2D3. Clinically, the disease is characterized by subcutaneous calcifi cations as well as periarticular calcifi cations located along the extensor surfaces of major joints, and may be associated with nephrolithia-sis in some cases. Familial tumoral calcinonephrolithia-sis has been found to result from mutations in several genes in-volved in phosphorus metabolism, including GALNT3, SAMD9, KLOTHO, and FGF23. Endosteal hyperostosis is another hereditary disease transmitted either in au-tosomal recessive or auau-tosomal-dominant fashion.
This disorder is characterized by asymmetric enlarge-ment of mandibulas and nasal bridge as well as mild frontal bone bossing.
6 7 – For details on hypo- and pseudohypopara-thyrodism, see Hypocalcemia.
8 – During either acute respiratory or metabolic acidosis, intracellular P is released into the extracel-lular fl uid. Thus, hyperphosphatemia and subsequent phosphaturia result.
9 – Acute P load with resulting hyperphosphate-mia may be observed after hypertonic sodium phos-phate enemas (especially in young children, or in those with an intestinal ileus) and also after inappro-priately prescribed intravenous P infusions. Oral so-dium phosphate laxatives are less likely to cause sus-tained hyperphosphatemia. Long-term treatment of osteopenia with biphosphonates may rarely lead to mild hyperphosphatemia and phosphaturia. Hyper-phosphatemia and phosphaturia associated with hy-percalcemia may appear in vitamin D intoxication.
Selected reading
Gelfand IM, Eugster EA, DiMeglio LA: Presentation and clinical progression of pseudohypoparathyroid-ism with multi-hormone resistance and Albright hereditary osteodystrophy: a case series. J Pediatr 2006;149:877–880.
Gupta A, Winer K, Econs MJ, Marx SJ, Collins MT:
FGF-23 is elevated by chronic hyperphosphatemia.
J Clin Endocrinol Metab 2004;89:4489–4492.
Langman CB: Disorders of phosphorus, calcium and vitamin D; in Avner ED, Harmon WE, Niaudet P (eds):
Pediatric Nephrology, ed 5. Philadelphia, Lippincott Williams & Wilkins, 2004, pp 237–254.
Topaz O, Shurman DL, Bergman R, Indelman M, Ratajczak P, Mizrachi M, Khamaysi Z, Behar D, Petronius D, Friedman V, Zelikovic I, Raimer S, Metzker A, Richard G, Sprecher E: Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis.
Nat Genet 2004;36:579–581.
Downloaded by: Univ. of California San Diego 198.143.33.65 - 8/6/2015 3:22:09 PM
100
Hypomagnesemia
/FEMg2+1
FEMg2+<2%
Symptoms 0
FEMg2+>2%
Renal losses
Acquired 5
Postobstructive diuresis Recovery from ATN Renal transplantation Drugs
Loop/thiazide diuretics Aminoglycosides Amphotericin B Cisplatinum Calcineurin inhibitors
Genetic 6
Gitelman syndrome Familial hypomagnesemia, hypercalciuria and nephrocalcinosis Isolated hypomagnesemia
(autosomal-dominant, autosomal-recessive) Autosomal-dominant hypoparathyrodism Decreased intake 2 Altered Mg2+distribution 3 Gastrointestinal losses 4
Hungry bone syndrome Refeeding
Diabetic ketoacidosis
Malabsorptive syndromes (celiac, IBD) Diarrhea
Short bowel syndrome Bowel resection Laxative abuse
Primary intestinal hypomagnesemia Malnutrition
Alcoholism
Low-magnesium food Parenteral fluids
Divalent ion metabolism
I. Eisenstein · P. Goodyer · I. Zelikovic
Hypomagnesemia101
Divalent ion metabolism
I. Eisenstein · P. Goodyer · I. Zelikovic
Hypomagnesemia1 – Magnesium ion (Mg2+), which is the second most common intracellular action, has an essential role in many biological processes. The kidney is the main organ responsible for Mg2+ homeostasis. Of total plasma Mg2+, 80% is fi ltered through the renal glom-eruli and more than 95% of the fi ltered Mg2+ is reab-sorbed by the renal tubule, mainly in the thick ascend-ing limb of the loop of Henle. Normal serum Mg2+ lev-els range from 0.62 to 1 mmol/l (1.5–2.4 mg/dl).
2 – Hypomagnesemia is often asymptomatic.
The signs and symptoms may be nonspecifi c and in-clude nausea, vomiting and muscle weakness. In more severe cases, symptoms are mostly of neuromuscular origin and include tremor, tetany, seizures, irritability and confusion. In addition, cardiac manifestation such as tachycardia, premature contractions and prolonged QT interval leading to fatal torsades de pointes may exist. Of note, hypomagnesemia may lead to hypocal-cemia and hypokalemia.
3 – Determination of urinary Mg2+ excretion is an important part of the evaluation of the patient with hy-pomagnesemia. To differentiate GI losses or reduced intake from renal losses, fractional excretion of Mg2+
(FEMg) should be determined. FEMg is calculated using the following formula: (UMg × Scr)/ ([0.8 × SMg] × Ucr) × 100 when UMg/Ucr and SMg/Scr are urine and serum Mg2+ and urine and serum creatinine concentrations, respectively. The factor 0.8 is used because only ap-proximately 80% of plasma Mg2+ is fi ltered through the renal glomeruli. The additional 20% are protein (mainly albumin)-bound and therefore are not fi lterable. Nor-mally, FEMg is under 2%.
4 – Poor oral intake is a rare cause of hypomag-nesemia in children. It may be seen along with other electrolyte defi ciencies.
5 – In hungry bone syndrome, seen mostly after parathyroidectomy, there is rapid bone formation leading to rapid intake of phosphorus, calcium and magnesium and hence to low plasma levels of these ions. The same clinical picture may be seen in the refeeding phase of malnourished children. In diabetic ketoacidosis, insulin therapy leads to magnesium in-take into the cells.
6 – The small intestine is the major site of mag-nesium absorption. Any pathological process leading to a disease in this part of the GI tract may cause mag-nesium defi ciency. Diarrhea has high magmag-nesium
con-tent (up to 200 mg/l) and thus may lead to hypomagne-semia. In steatorrhea, hypomagnesemia can ensue due to the formation of magnesium lipid-salts. Primary intestinal hypomagnesemia with secondary hypocal-cemia is a rare autosomal-recessive disorder. Patho-physiology is related to impaired intestinal absorption of magnesium accompanied by renal magnesium wasting as a result of a reabsorption defect in the dis-tal convoluted tubule. The disease is caused by muta-tions in the gene encoding TRPM6, a member of the transient receptor potential family of cation channels which is expressed in the small intestine and the distal convoluting tubule. Primary intestinal hypomagnese-mia with secondary hypocalcehypomagnese-mia manifests clinically as refractory seizures in infancy with very low serum calcium and magnesium levels.
7 – Conditions leading to renal magnesium wast-ing include postobstructive diuresis and the recovery phase of ATN. In children who received renal trans-plantion, hypomagnesemia is usually the result of therapy with calcineurin inhibitors [cyclosporine A, ta-crolimus (FK-506)]. Other drugs causing hypomagne-semia are listed in the algorithm.
8 – There are several hereditary disorders lead-ing to renal magnesium losses. In Gitelman syndrome, a variant of Bartter syndrome, patients present during late childhood or adolescence with muscle weakness and tetany. Typical laboratory fi ndings include, in addi-tion to hypomagnesemia, hypokalemia, metabolic al-kalosis and hypocalciuria. Although the most common genetic defect leading to GS is a mutation in the gene encoding the NaCl cotransporter in the distal convo-luted tubule, a defect in the Cl- channel ClCKb may also lead to Gitelman syndrome. Familial hypomagne-semia, hypercalciuria and nephrocalcinosis, previous-ly called Michellis-Castrillo syndrome, is an autosomal-recessive disorder causing severe renal magnesium and calcium wasting leading to hypomagnesemia and nephrocalcinosis with normal serum calcium levels.
The typical patient presents in early childhood with seizures, tetany, recurrent urinary tract infections, kid-ney stones, polyuria and polydipsia. Renal failure de-velops later in most patients. Extrarenal manifesta-tions may include ocular involvement. The disease is due to a mutation in the gene encoding paracel lin-1, a member of the claudin family of tight junction pro-teins located in the thick ascending limb of the loop of Henle. Isolated hypomagnesemia (autosomal-domi-nant) is an extremely rare disorder of renal magne-sium wasting. Patients with the autosomal-dominant
variant are usually asymptomatic. An additional typi-cal laboratory fi nding is hypotypi-calciuria. The genetic defect is in the ␥-subunit of the Na-K-ATPase trans-porter located in the basolateral membrane of the dis-tal convoluting tubule. Autosomal-dominant hyper-parathyroidism is caused by an activating mutation of the calcium-sensing receptor in the parathyroid gland.
The mutation in this receptor, which also senses mag-nesium levels, leads to renal magmag-nesium and calcium wasting. PTH levels are inappropriately low for the de-gree of hypocalcemia. Very recently, a defect in the gene encoding epidermal growth factor has been im-plicated in hereditary renal magnesium wasting.
Selected reading
Cole DE, Quamme GA: Inherited disorders of renal magnesium handling. J Am Soc Nephrol 2000;11:
1937–1947.
Greenbaum LA: Electrolyte and acid-base disorders;
in Behrman RE, Kliegman RM, Jenson HB (eds):
Nelson Textbook of Pediatrics, ed 17. Philadelphia, Saunders, 2004.
Groenestege WM, Thebault S, van der Wijst J, van den Berg D, Janssen R, Tejpar S,
van den Heuvel LP, van Cutsem E, Hoenderop JG, Knoers NV, Bindels RJ: Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypo-magnesemia. J Clin Invest 2007;117:2260–2267.
Kang JH, Choi HJ, Cho HY, Lee JH, Ha IS, Cheong HI, Choi Y: Familial hypomagnesemia with hypercalci-uria and nephrocalcinosis associated with CLDN16 mutations. Pediatr Nephrol 2005;20:1490–1493.
Riveira-Munoz E, Chang Q, Bindels RJ, Devuyst O:
Gitelman‘s syndrome: towards genotype-pheno-type correlations? Pediatr Nephrol 2007;22:326–332.
Rodríguez Soriano J: Tubular disorders of electro-lyte regulation; in Avner ED, Harmon WE, Niaudet P (eds): Pediatric Nephrology, ed 5. Philadelphia, Lippincott Williams & Wilkins, 2004, pp 729–757.
Schlingmann KP, Konrad M, Seyberth HW: Genetics of hereditary disorders of magnesium homeostasis.
Pediatr Nephrol 2004;19:13–25.
Zelikovic I: Molecular pathophysiology of tubular transport disorders. Pediatr Nephrol 2001;16:
919–935.
Downloaded by: Univ. of California San Diego 198.143.33.65 - 8/6/2015 3:22:09 PM
102
Hypercalciuria
Urolithiasis, hematuria, dysuria
Urine calcium/creatinine ratio 24-hour collection or spot /
>0.2 mg/mg (0.56 mmol/mmol in children older than 2 years Abnormal
History and physical examination 0 Family history 1
Dietary history 2 Medication history 3
Defer evaluation if patient has urinary tract infection 4
Repeat urinary testing including 24-hour collection for calcium, sodium, citrate, creatinine:
onsider testing uric acid and oxalate levels 5
Urine calcium/creatinine
>0.2 mg/mg Hypercalciuria
<0.2 mg/mg Normal
Urine citrate
<400 mg/mg creatinine (Consider distal RTA)
<0.2 mg/mg (0.56 mmol/mmol) in children older than 2 years Normal
Ultrasound
Normal
Blood tests
Electrolytes, bicarbonate, pH, calcium, phosphorus, magnesium, PTH and vitamin D metabolites
Idiopathic hypercalciuria
High fluid intake 6 Reduced Na+ intake High K+and low oxalate diet Consider thiazides
Possible causes of secondary hypercalciuria (table) Hypercalcemia
Hypophosphatemia Metabolic acidosis Hypomagnesemia Renal tubular acidosis Dent disease Bartter syndrome Urolithiasis Nephrocalcinosis
Divalent ion metabolism
F.B. Stapleton · J. Smith
Hypercalciuria103
Divalent ion metabolism
F.B. Stapleton · J. Smith
Hypercalciuria1 – Whenever possible, the diagnosis of hyper-calciuria should be made on the basis of a 24-hour uri-nary excretion. In young children, timed uriuri-nary collec-tions may be impractical or impossible. Urinary cal-cium excretion in younger children is estimated by use of the ratio of urinary calcium to creatinine on a fasting spot urine. Normal calcium excretion during childhood has been defi ned as <4 mg/kg per day while eating a routine diet. Normal values for fasting spot or 24-hour urine calcium/creatinine ratio for children are: 0–6 months is <0.8 mg/mg, 7–12 months is <0.6 mg/mg, and >2 years is <0.2 mg/mg. Use of random urinary collections may be misleading. The urine calcium to creatinine ratio may increase by 40% or as high as 0.28 following a meal. A fi rst morning fasting collection along with a postprandial sample can provide consid-erable information. If only a single random sample is available, it would be desirable to collect a sample 2–4 h following a meal in which milk is given. In such a sample, if the ratio of urinary calcium to creatinine is
<0.2, further evaluation for hypercalciuria is not neces-sary.
2 – Hypercalciuria is most often considered in the evaluation of urolithiasis, hematuria, or less com-monly dysuria. The purpose is to identify idiopathic or secondary causes of hypercalciuria.
3 – As many as 80% of patients with idiopathic hypercalciuria have a family member with urolithiasis.
In familial idiopathic hypercalciuria, an autosomal-dominant pattern of inheritance has been postulated.
When males in multiple generations have hypercalci-uria, urinary stones, and proteinuria (with or without renal failure), one should suspect X-linked hypercalciu-ric nephrolithiasis (Dent disease) (table).
4 – A careful dietary history should be obtained in all children with hypercalciuria to ascertain if dietary factors might account for the fi nding. High intake of dietary sodium and/or protein may increase the uri-nary excretion of calcium.
5 – Some of the medications that have been associated with hypercalciuria include furosemide, corticosteroids, vitamin D and methylxanthines.
6 – Diagnostic studies for hypercalciuria should be deferred if the patient has a urinary tract infection, as pyelonephritis increases urinary calcium excretion.
7 – Once an abnormal value is discovered, it should be re-confi rmed and examined in relationship to urinary sodium excretion. If the urinary collections suggest a high dietary sodium intake, a collection fol-lowing 2–4 weeks of sodium restriction (2–3 g sodium per day) is indicated. Additional urinary studies should be performed including creatinine level, to establish the adequacy of the collection and normalization of values, and citrate level to evaluate for renal tubular acidosis. Urinary uric acid and oxalate levels should be tested if indicated. Both, hyperuricosuria and hyperox-aluria may coexist with hypercalciuria. Normal urinary values for school-age children: calcium <4 mg/kg/day;
citrate >400 mg/g creatinine; uric acid <0.56 mg/dl GFR; oxalate <50 mg/1.73 m2/day; cystine <60 mg/
1.73 m2/day.
8 – When idiopathic hypercalciuria is confi rmed, the next step is to assess whether dietary manipula-tions can normalize calcium excretion. High fl uid in-take is mandatory. A reduced sodium, high potassium, and low oxalate diet is recommended for children with hypercalciuria. Sodium restriction is indicated be-cause of the well-known calciuric effect of high dietary sodium intake. Increased potassium intake may re-duce urine calcium excretion. For children unrespon-sive to dietary sodium restriction and potassium sup-plementation, hydrochlorothiazide (1–2 mg/kg/day) and/or citrate therapy may be helpful. Dietary calcium restriction is not recommended for children with hy-percalciuria especially in the light of reports of osteo-penia in affected children, as well as increased urinary oxalate excretion with low-calcium diets.
Selected reading
Frick KK, Bushinsky DA: Molecular mechanisms of primary hypercalciuria. J Am Soc Nephrol 2003;14:
1082–1095.
Gillespie RS, Stapleton FB: Nephrolithiasis in children. Pediatr Rev 2004;25:131–138.
Southwest Pediatric Nephrology Study Group:
Idiopathic hypercalciuria: association with isolated hematuria and risk urolithiasis in children.
Kidney Int 1990;37:807–811.
Stapleton FB, Kroovand RL: Stones in childhood;
in Coe FL, Favus MJ, Pan CYC, et al (eds): Kidney Stones: Medical and Surgical Management.
Philadelphia, Lippincott-Raven, 1996, pp 1065–1080.
Stapleton FB, Noe HN, Jerkins GR, et al: Hyper-calciuria in children with urolithiasis. Am J Dis Child 1982;136:675–678.
Stapleton FB. McKay CP, Noe HN: Urolithiasis in children: the role of hypercalciuria. Pediatr Ann 1987;16:980–992.
Thomas SE, Stapleton FB: Leave no stone unturned:
understanding the genetic basis of calcium-contain-ing stones in children. Adv Pediatr 2000;47:199–221.
Table. Selected causes of hypercalciuria and urolithiasis Increased intestinal calcium absorption
Vitamin D excess Renal tubular dysfunction Renal tubular phosphate leak
Impaired renal tubular calcium absorption Hypercalciuric hypocalcemia
Hypomagnesemia-hypercalciuria syndrome Type 1 (distal) renal tubular acidosis Dent disease
Juvenile rheumatoid arthritis Other
Familial idiopathic hypercalciuria Drugs (certain diuretics, corticosteroids) Urinary tract infection
Williams syndrome
Increased renal prostaglandin E2 production Hypercalcemia
Hypophosphatemia Glycogen storage disease
Downloaded by: Univ. of California San Diego 198.143.33.65 - 8/6/2015 3:22:09 PM
104