Bone mineral content reduction in youth with surgical form of Schistosomiasis mansoni: factors involved in the pathogenesis

Redução do conteúdo mineral ósseo em jovens portadores de esquistossomose mansônica cirúrgica: fatores envolvidos na patogênese

Abstracts

Thirty two children and adolescents from 14 to 20 years of age, suffering from hepatosplenic schistosomiasis mansoni and bleeding esophageal varicose veins, were evaluated for bone mineral density (BMD), before undergoing medical and surgical treatment. The surgical protocol was splenectomy, autoimplantation of spleen tissue into a pouch of the major omentum and ligature of the left gastric vein. Follow up of these patients’ ranges from one to ten years with a mean of five years. The BMD was measured at the lumbar spine (L2 - L4) through the dual energy absorptionmetry X-ray (DEXA), using a LUNAR DPX-L densitometer. The degree of Symmers´ fibrosis was assessed by semiautomatic hystomorphometry. In eleven patients, the serum magnesium was measured before an intravenous overload of this ion and subsequently after eight and twenty four hours. Urine was collected 24 hours before and 24 hours after the magnesium overload. Deficiency of magnesium was considered when the uptake of this ion was greater than 40%. There was a significant trend of association between the status of bone mineral content and the Symmers´ fibrosis degree (c² = 6.606 R = 0.01017). There was also a moderate agreement between the greater fibrosis densities ( > the mean percentage) and bone mineral deficits. Although the normal bone mineral content was more found among the patients with better hepatic functional reserve, the results did not reach statistical significance. There was a marked magnesium retention (>95%) in one patient who had severe osteoporosis and a slight depletion (<5%) in another patient, who presented no bone mineral deficit. It was concluded that the patients included in this series, showed an important BMD deficit, specially among the females which has had a significant improvement after medical and surgical treatment. Bone mineral deficit was associated with the degree of Symmers´ fibrosis. Magnesium depletion was present in two out of eleven patients. It is speculated that magnesium supplementation may be warranted to forestall the progression of bone mineral deficit in patients with more impaired hepatic functional reserve.

Schistosomiasis mansoni; Symmers´ fibrosis; Hystomorphometry; Hepatic functional reserve; Magnesium status; Bone mineral density

Trinta e duas crianças e adolescentes, de 14 a 20 anos de idade, portadores de esquistossomose mansônica na forma hepatoesplênica e varizes sangrentas do esôfago, foram avaliadas para conteúdo mineral ósseo (BMD), antes de serem submetidas a tratamento clínico-cirúrgico. O protocolo cirúrgico constou de esplenectomia, ligadura da veia gástrica esquerda e autoimplante de tecido esplênico em bolsa no omento maior. O seguimento pós-operatório desses pacientes varia entre um e dez anos, com uma média de cinco anos. O BMD foi medido na vértebra lombar (L2-l4), através de aparelho de raio-X de dupla absorção e energia (DEXA), usando um densitômetro modelo LUNAR DPX-L. O grau de fibrose de Symmers foi avaliado por histomorfometria semi-automática. Em onze pacientes, o magnésio sérico foi medido antes e subseqüentemente oito e vinte e quatro horas após infusão desse íon. A deficiência de magnésio foi considerada quando a retenção desse íon fosse maior que 40%. Houve uma tendência à associação entre o padrão do conteúdo mineral ósseo e o grau da fibrose de Symmers (c² = 6,606 R = 0,01017). Houve ainda uma moderada concordância entre o maior grau de densidade fibrótica (acima da percentagem média) e o déficit mineral ósseo. Embora o conteúdo mineral ósseo normal estivesse mais evidente entre os pacientes com melhor reserva funcional hepática, os resultados não alcançaram significação estatística. Houve uma acentuada retenção de magnésio infundido (>95%) em uma paciente que tinha osteoporose e uma retenção desse íon discretamente acima de 40% em um paciente que não apresentava déficit conteúdo mineral ósseo. Em conclusão, os pacientes incluídos nesta série mostravam um importante déficit de BMD, especialmente entre as meninas, que obtiveram melhora significativa após tratamento clínico e cirúrgico. O déficit mineral ósseo desses pacientes estava associado ao grau de fibrose de Symmers. Depleção de magnésio esteve presente em dois de onze desses pacientes. Pode-se especular que a suplementação de magnésio possa ser útil para deter a progressão do déficit do conteúdo mineral ósseo nos pacientes com reserva funcional hepática mais comprometida.

Esquistossomose mansônica; Fibrose de Symmers; Histomorfometria; Reserva funcional hepática; Níveis de magnésio; Densitometria óssea; Conteúdo mineral ósseo

9 – ORIGINAL ARTICLE

BONE MINERAL CONTENT REDUCTION IN YOUTH WITH SURGICAL FORM OF SCHISTOSOMIASIS MANSONI: FACTORS INVOLVED IN THE PATHOGENESIS¹

Carlos Teixeira Brandt²

Antônio Marcelo Gonçalves de Souza³

Maria Virgínia da Motta Braga⁴

Karina Leal Reis de Melo⁴

Karina de Oliveira Andrade Marques⁴

Andréa Dantas Sena⁴

Fernando Almeida⁵

Brandt CT, Souza AMG, Braga MVM, Melo KLR, Almeida F, Marques KOA, Sena AD. Bone mineral content reduction in youth with surgical form of Schistosomiasis mansoni: factors involved in the pathogenesis. Acta Cir Bras [serial online] 2001 Jan-Mar;16(1). Available from: URL: http://www.scielo.br/acb.

ABSTRACT: Thirty two children and adolescents from 14 to 20 years of age, suffering from hepatosplenic schistosomiasis mansoni and bleeding esophageal varicose veins, were evaluated for bone mineral density (BMD), before undergoing medical and surgical treatment. The surgical protocol was splenectomy, autoimplantation of spleen tissue into a pouch of the major omentum and ligature of the left gastric vein. Follow up of these patients’ ranges from one to ten years with a mean of five years. The BMD was measured at the lumbar spine (L2 - L4) through the dual energy absorptionmetry X-ray (DEXA), using a LUNAR DPX-L densitometer. The degree of Symmers´ fibrosis was assessed by semiautomatic hystomorphometry. In eleven patients, the serum magnesium was measured before an intravenous overload of this ion and subsequently after eight and twenty four hours. Urine was collected 24 hours before and 24 hours after the magnesium overload. Deficiency of magnesium was considered when the uptake of this ion was greater than 40%. There was a significant trend of association between the status of bone mineral content and the Symmers´ fibrosis degree (c² = 6.606 R = 0.01017). There was also a moderate agreement between the greater fibrosis densities ( > the mean percentage) and bone mineral deficits. Although the normal bone mineral content was more found among the patients with better hepatic functional reserve, the results did not reach statistical significance. There was a marked magnesium retention (>95%) in one patient who had severe osteoporosis and a slight depletion (<5%) in another patient, who presented no bone mineral deficit. It was concluded that the patients included in this series, showed an important BMD deficit, specially among the females which has had a significant improvement after medical and surgical treatment. Bone mineral deficit was associated with the degree of Symmers´ fibrosis. Magnesium depletion was present in two out of eleven patients. It is speculated that magnesium supplementation may be warranted to forestall the progression of bone mineral deficit in patients with more impaired hepatic functional reserve.

SUBJECT HEADINGS: Schistosomiasis mansoni. Symmers´ fibrosis. Hystomorphometry. Hepatic functional reserve. Magnesium status. Bone mineral density.

INTRODUCTION

Schistosomiasis mansoni still represents an important problem of public health in Brazil, especially in the northeastern region where prevalence of this disease is very high¹. Upper digestive bleeding is the most dangerous symptom in the very severe forms of this condition², however, in children, hypersplenism and changes in the somatic development are also important³.

It has been demonstrated that there is, in children, adolescents and young adults with hepatosplenic surgical manifestation of this disease, deficit of the bone mineral content. It has also been showed that medical treatment of the parasite, followed by surgical treatment of the portal hypertension is associated with an improvement of the bone mineral content. However, some of the patients still present with bone mineral deficit after adequate medical and surgical treatments^4,5.

In cirrhotic patients, bone mineral content is reduced and may be associated with hepatic functional reserve. It has been demonstrated, in these patients, that bone mineral reduction is associated with serum magnesium concentration and uptake. It has also been showed that supplementation with oral magnesium improves the degree of bone mineral deficit⁶.

The aim of this investigation was to study the possible factors involved in the pathogenesis of the bone mineral deficit in young patients with surgical form of the Schistosomiasis mansoni disease. It was studied the following in these patients: 1 – the possible association of the Symmers´ fibrosis degree and bone mineral content; 2 – the possible association of the hepatic functional reserve and bone mineral content; and 3- the possible association of the magnesium serum levels and uptake with bone mineral content.

METHODS

Patients

Thirty two young patients, from twelve to twenty years of age, with proven severe form of hepatosplenic Schistosomiasis mansoni, cared for at " Hospital das Clínicas – Health Sciences Center – Federal University of Penambuco, were included in this investigation. 21 patients were males and 11 females, the ages ranged from 14 to 20 years. All patients came from endemic regions for schistosomiais mansoni. These patients presented at the time of admission with: somatic development deficit; large and hard liver; and voluminous spleen. They had had several episodes of upper digestive bleeding due to rupture of esophageal varicose veins. Positive Kato Katz was positive in 30 patients, however, in two patients’ rectal biopsy and quantitative oogram was necessary to prove the Schistosomiasis mansoni infection.

These patients received medical treatment with oxamniquine (20mg/kg single doses). Thirty days after this treatment they underwent the following surgical treatment: splenectomy; ligature of the left gastric vein; and auto-implantation of spleen tissue into a pouch of the major omentum.

Follow up of these patients’ ranges from one to ten years with a mean of five years.

Procedures

Bone mineral content was measured at the lumber spine (L2 – L4) through a dual energy absorptionmetry X-ray (DEXA), using a LUNAR DPX-L densitometer. The BMD was considered normal until 0.99 Standard Deviation (SD) considering the mean line of the control health curve accepted as normal. Osteopenia was considered when the deficit was between 1.0 and 2.5 SD of this mean line, while osteoporosis was considered when the mineral density deficit was greater than 2.5 SD.

The assessment of the Symmers´ fibrosis degree was done in wedge liver biopsies obtained at the operation time. The histological slide sections were stained by Masson´s trichrome. Histomorphometry studies were done at Immunopatholy Laboratory Keiso Asami (LIKA). A semiautomatic analyzing system was used. A Leica, Q500 MC ( Leica Cambridge Ltda., Cambridge, England ) was used for processing the images. It was studied, at randomly, ten fields, measuring each one 1,679.36 m² corresponding to a total area of 1.68 mm² of the histological section. The area occupied by the Symmers´ fibrosis was measured directly and then divided by the total area of the field and the results were expressed in percentages. The end result was expressed as a mean percentage of fibrosis obtained from ten consecutive measurements.

The patients with mean percentages of Symmers´ fibrosis between the mean ± 1SD were classified as grade II. Those with mean percentages lower than the mean - 1SD were classified as grade I. On the other hand, those with mean percentages greater than the mean + 1SD were classified as grade III.

The Child criteria for assessment of hepatic functional reserve were used. In addition the prothrombin time was also assessed.

In eleven patients, the magnesium serum levels and uptake were measured as follows: twenty-four hours collection of urine was done for determining the normal magnesium excretion. After a night of nil ingestion by mouth serum basal level of magnesium was measured. Then an intravenous magnesium overload (6mg of elementary magnesium per kilogram of body weight) was infused. Serial levels of magnesium were measured after twelve and twenty four hours from the overload. Twenty-four hours collection of urine was repeated and urinary magnesium level was assessed for determining the magnesium uptake. Deficiency of magnesium was considered when the uptake of this ion was greater than 40%.

Data analysis

The quantitative results were expressed by their means and respective standard deviations (SD). The qualitative data were expressed by their frequencies in percentages. Paired "t" Student test was used for measuring differences between two means and X ² test was used for assessing differences between frequencies. The measure of agreement was done by kappa ( K ) test. The null hypothesis was rejected at the level of R < 0.05.

Ethical consideration

The ethical committee of the Hospital das Clínicas –Health Sciences Center – Federal University of Pernambuco approved this study. The patients and or their parents, included in this investigation, have signed the consent form after full explanation of the study.

RESULTS

The patient distribution relating the Symmers´fibrosis degree and bone mineral content are showed in tables 1, 2 and 3.

As regard to the hepatic functional reserve, before medical and surgical treatments 10 patients were classified as presenting good risk ( A ), and 22 as moderate risk ( B ). Nowadays, 16 patients are Child A and 16 Child B. However not reaching statistical significance (Yates corrected: c² = 1.62 R = 0.2031708), there has been, overall, an improvement in the status of hepatic functional reserve in these patients. Similarly, there has been an improvement in the status of bone mineral content. Before treatments no patient had normal bone mineral content ( N ) and nowadays, nine patients are normal as regard to their bone mineral content.

The patient distribution relating the status of the hepatic functional reserve is expressed in table 4.

The magnesium serum concentration mean before the overload was 2.10 + 0.19mg/dl. Eight hours after the overload, it was 2.45 + 0.13 mg/dl. Twenty four hours after the overload, it was 2.11 + 0.32 mg/dl. There were significantly statistical differences between the pre and the eight hour ("t" = 3.954 R < 0.01) and twenty four hour ("t" = 2.922 R < 0.02) post overload serum magnesium means. However, there was no statistical difference ("t" = 0.088 R > 0.05) between the eight and the twenty four hour post overload serum magnesium means.

The post overload 24 hour urinary magnesium excretion mean was, significantly, greater than the pre overload (272.5 + 104.9 mg versus 99.54 + 41.2 mg - "t" = 4.422 R < 0.01).

As regard to the magnesium uptake, one patient who had osteoporosis showed a severe magnesium depletion (retention greater than 95%). Another patient, who had no bone mineral deficit, showed a magnesium retention just above 40%. The rest of the patients showed magnesium uptake inside the limits of the normal variation. The mean retention of magnesium was 34.4% + 28.8%.

DISCUSSION

Similarly to patients with cirrhosis, there was a significant trend showing linear association between the hystomorphometric degree of Symmers´ fibrosis and bone mineral deficit. It was observed that no patients with marked fibrosis (G III) presented normal bone mineral content. On the other hand, no patient with slight portal fibrosis (G I) presented osteoporosis. It was showed that, when the patients were divided into two groups: 1 – equal to or greater than the mean percentage of Symmers´ fibrosis; and 2 – smaller than the mean percentage of Symmers´ fibrosis, there was a moderate strength of agreement between these two variables.

It was observed an improvement of the hepatic functional reserve when it is compared the pre treatment parameters and the last evaluation of the liver status. It is likely that the main reason for this change is a positive increment in the somatic development as we have proved before⁷. We have also reported a significant improvement of the hepatic functional reserve in another series of patients presenting similar stage of the disease who have undergone identical protocol of treatments⁸.

Bone mineral deficit has been associated with liver disease in adults, but less so in children. Furthermore, there has been few studies on Schistosomiasis mansoni^4,5. Patients with low hepatic functional reserve tend to develop osteopenia or osteoporosis, and to decline the serum levels of 25-OHD and 1.25(OH)₂D and osteocalcin^9,10,11,12. Coincident with these changes, there is a decline of the calcium absorption¹³. All these factors are involved in bone mineral deficit in patients with chronic liver disease.

It has been showed that magnesium depletion is extremely common in children with chronic colestasis⁶ and balance studies in infants with biliary atresia suggest poor calcium and magnesium absorption¹⁴. However, there is no report on magnesium serum levels in patients with hepatosplenic Schistosomiasis mansoni. From the results it became evident that magnesium depletion is less important in patients suffering from hepatosplenic S. mansoni as compared to patients with cirrhosis. The probable explanation lies in the well documented preservation of the hepatic functional reserve in patients with pure Manson’s disease, as it is observed in the patients of this series, after undergoing medical and surgical treatment.

It has been demonstrated that neither serum nor erythrocyte magnesium concentration correlates well with tissue pools^15,16. However, magnesium serum concentration seems to be related to metabolic bone diseases in chronic cholestasis. Bone mineral content, on the other hand, is likely to be a good parameter for assessing the hepatic functional reserve, either in cirrhotic as well as in hepatosplenic Schistosomiasis mansoni patients. In this series, there was a great dispersion of magnesium retention and it was not clear if magnesium depletion is a frequent phenomenon.

CONCLUSION

Based upon the preliminary results from this investigation and from the study on cirrhotic patients⁶ it can be speculated that magnesium supplementation may be warranted to forestall the progression of bone mineral deficit in patients with Schistosomisasis mansoni and more impaired hepatic functional reserve.

REFERENCES

1. Brandt CT, Tavares Maciel DS, Caneca OAF. Splenectomy associated with ligature of the left gastric vein in children with surgical schistossomiasis: analysis of the hepatic functional reserve. Acta Cir Bras 1997;12:150-3.

2. Kelner S. Critical evaluation of surgical treatment of schistosomotic portal hypertension. Memórias do Instituto Oswaldo Cruz 1992;87(Supl 4):357-8.

3. Brandt CT, Tavares Maciel DS, Caneca OAF. Esplenose associada ao tratamento cirurgico da hipertensão porta esquistossomótica na criança: avaliação de dez anos. An Fac Med Univ Fed Pernamb Recife 1999;44:15-20.

4. De Souza AMG, Brandt CT, Almeida F. Densidade mineral óssea (BMD) em crianças esquistossomóticas na forma hepatoeslênica com indicação cirúrgica. An Fac Med Univ Fed Pernamb Recife 1993;38:9-11.

5. Brandt CT, De Souza AMG, Braga MVM, Melo KLR, Almeida F. Bone mineral density in children and adolescents with hepatosplenic mansonic schistossomiasis and esophageal varices who underwent splenectomy and ligature of the left gastric vein. Acta Cir Bras 1999; http://www.scielo.br/acb.

6. Heubi JE, Higgins JV, Argao EA, Sierra RI & Specker BL. The role of magnesium in the pathogenesis of bone disease in childhood cholestatic liver disease: a preliminary report. J Pediatr Gastroenterol Nutrition 1997;25:301-6.

7. Brandt CT, Maciel DT, Alexandre SA. Esquistossomose hepatoesplênica em crainças: desenvolvimento pondo-estatural após tratamento cirúrgico. An Fac Med Univ Fed Pernamb Recife 1995;40:106-10.

8. Brandt CT. Splenectomy associated with ligature of the left gastric vein in children with surgical schistosomiasis: analysis of the hepatic functional reserve. Acta Cir Bras 1997;12:150-3.

9. Mitchison HC, Malcolm AJ, Bassendine MF, James OFW. Metabolic bone disease in primary biliary cirrhosis at presentation. Gastroenterology 1988;94:463-70.

10. Diblle JB, Sheridan, Losowsky MS. A survey of vitamin D deficiency in gastrointestinal and liver disorders. Quart J Med 1984;209:119-34.

11. Bible DD, Gee E, Hallora B, Haddad JG. Free I, 25-dihydroxy vitamin D levels in serum from normal subjects, pregnant subjects and subjects with liver disease. J Clin Invest 1984;74:1966-71.

12. Pietschmann P, Resch N, Muller CH, et al. Decreased serum osteocalcin in patients with liver cirrhosis. Bone Mineral 1990;8:103-8.

13. Bengoa JM, Sitrin MD, Meredith S, et al. Intestinal calcium absorption and vitamin D status in chronic cholestatic liver disease Hepatology 1984;21:261-5.

14. Kobayashi A, Utsunomiya T, Ohbe Y, Nagashima Y. Intestinal absorption of calcium and magnesium in hepatobiliary disease in infancy. Arch Dis Child 1974;49:90-6.

15. Reinhart RA. Magnesium metabolism: a review with special reference to the relationship between intracellular content and serum levels. Arch Int Med 1988;148:2415-20.

16. Elin RJ, Hosseini J. Magnesium content of mononuclear cells. Clin Chem 1985;31:377-80.

Brandt CT, Souza AMG, Braga MVM, Melo KLR, Almeida F, Marques KOA, Sena A. Redução do conteúdo mineral ósseo em jovens portadores de esquistossomose mansônica cirúrgica: fatores envolvidos na patogênese. Acta Cir Bras [serial online] 2001 Jan-Mar;16(1). Available from: URL: http://www.scielo.br/acb.

RESUMO: Trinta e duas crianças e adolescentes, de 14 a 20 anos de idade, portadores de esquistossomose mansônica na forma hepatoesplênica e varizes sangrentas do esôfago, foram avaliadas para conteúdo mineral ósseo (BMD), antes de serem submetidas a tratamento clínico-cirúrgico. O protocolo cirúrgico constou de esplenectomia, ligadura da veia gástrica esquerda e autoimplante de tecido esplênico em bolsa no omento maior. O seguimento pós-operatório desses pacientes varia entre um e dez anos, com uma média de cinco anos. O BMD foi medido na vértebra lombar (L2-l4), através de aparelho de raio-X de dupla absorção e energia (DEXA), usando um densitômetro modelo LUNAR DPX-L. O grau de fibrose de Symmers foi avaliado por histomorfometria semi-automática. Em onze pacientes, o magnésio sérico foi medido antes e subseqüentemente oito e vinte e quatro horas após infusão desse íon. A deficiência de magnésio foi considerada quando a retenção desse íon fosse maior que 40%. Houve uma tendência à associação entre o padrão do conteúdo mineral ósseo e o grau da fibrose de Symmers (c² = 6,606 R = 0,01017). Houve ainda uma moderada concordância entre o maior grau de densidade fibrótica (acima da percentagem média) e o déficit mineral ósseo. Embora o conteúdo mineral ósseo normal estivesse mais evidente entre os pacientes com melhor reserva funcional hepática, os resultados não alcançaram significação estatística. Houve uma acentuada retenção de magnésio infundido (>95%) em uma paciente que tinha osteoporose e uma retenção desse íon discretamente acima de 40% em um paciente que não apresentava déficit conteúdo mineral ósseo. Em conclusão, os pacientes incluídos nesta série mostravam um importante déficit de BMD, especialmente entre as meninas, que obtiveram melhora significativa após tratamento clínico e cirúrgico. O déficit mineral ósseo desses pacientes estava associado ao grau de fibrose de Symmers. Depleção de magnésio esteve presente em dois de onze desses pacientes. Pode-se especular que a suplementação de magnésio possa ser útil para deter a progressão do déficit do conteúdo mineral ósseo nos pacientes com reserva funcional hepática mais comprometida.

DESCRITORES: Esquistossomose mansônica. Fibrose de Symmers. Histomorfometria. Reserva funcional hepática. Níveis de magnésio. Densitometria óssea. Conteúdo mineral ósseo.

Address for correspondence:

Carlos Teixeira Brandt

Univ. Federal Pernambuco – Centro Ciências Saúde

Av. Moraes Rêgo, s/n HC – Bloco A

Recife – PE

50670-420

Tel/Fax: [phone]

Data do recebimento: 05/09/2000

Data da revisão: 02/11/2000

Data da aprovação: 13/12/2000

1

- From the Department of Surgery – Health Sciences Center, Federal University of Pernambuco.

2 – Full Professor – Pediatric Surgery, Federal University of Pernambuco.

3 – Associated Professor – Orthopedic Surgery, Federal University of Pernambuco.

4 – Brazilian National Research Council (CNPq) Scholarship, UFPE.

5 – Medical Doctor - Nuclear Medicine.

Publication Dates

• Publication in this collection
  11 Sept 2003
• Date of issue
  Mar 2001

History

• Accepted
  13 Dec 2000
• Reviewed
  02 Nov 2000
• Received
  05 Sept 2000