Multidrug-resistant tuberculosis: prevalence

Multidrug-resistant tuberculosis (MDR-TB) and extensively-drug resistant Tuberculosis (XDR TB) has become the emerging diseases and health problems in the world. (Kritski et al., 1996, Becerra et al., 2011, Schaaf et al., 2003, Rahajoe et al., 2008). Children with tuberculosis contact investigation can only detect relatively active cases of TB (TB hospital) in small amounts in areas with low incidence, compared to areas with high incidence. (Bayona et al., 2003, Behr et al., 1998, Noertjojo et al., 2002, Topley et al., 1996, Kuaban et al., 1996, Marks et al., 2000). Children at high risk of contracting TB from household contacts (household) with MDR-TB so that both the identification of TB infection (latent TB) or TB hospital should be carried out systematically by taking into account various relevant factors. 

World Health Organization (WHO) estimates that one third of world population infected with M.tb, especially in Africa, Asia and Latin America child to the proportion of TB cases per year is 5-6%. Indonesia is currently ranked fifth of 22 countries with the highest number of TB sufferers in the world. According to WHO's Global Tuberculosis Control Report 2009, there were 528,063 new cases of TB incidence of 102 new smear positive cases per 100,000 population in 2007. Number of TB children aged <15 years in developing countries reached 15% while in developed countries 5-7% of all cases. An increasing number of TB cases in 1985-1992 occurred in the age of 25-44 years (54.5%), 0-4 years (36.1%) and 5-12 years (38.1%). TB cases in 2005 is estimated to rise 58% from 1990, 90% of them occur in developing countries. (Rahajoe et al., 2008). 

In children under five, sick of TB occurred in 8.5% of children and latent TB infection at 30.4%. (Morrison et al., 2008). In all age groups, 4.5% of household contacts suffering from TB and 51.4% had latent TB infection. Several studies in Africa reported a 14-45% household contacts of children suffering from latent TB infection and 23-34% of TB illness, with tracking done actively (Beyers et al., 1997). The proportion of latent TB infection were reported higher in Asia (30-70%), but the incidence of TB illness was lower (3-16.4%) than that reported in Africa. (Nguyen et al., 2009). 

Cases of MDR-TB is a major issue which, according to WHO, TB control if not true, the prevalence of MDR-TB was 5.5% whereas with the correct control of the implementation strategy of directly observed treatment short course (DOTS), the prevalence of MDR-TB only 1.6%. (Rahajoe et al., 2008). The data of MDR-TB official in Indonesia until saai not currently exist. (Rahajoe et al., 2008).

BAYONA, J., CHAVEZ-PACHAS, A. M., PALACIOS, E., LLARO, K., SAPAG, R. & BECERRA, M. C. 2003. Contact investigations as a means of detection and timely treatment of persons with infectious multidrug-resistant tuberculosis. Int J Tuberc Lung Dis, 7, S501-9.

BECERRA, M. C., APPLETON, S. C., FRANKE, M. F., CHALCO, K., ARTEAGA, F., BAYONA, J., MURRAY, M., ATWOOD, S. S. & MITNICK, C. D. 2011. Tuberculosis burden in households of patients with multidrug-resistant and extensively drug-resistant tuberculosis: a retrospective cohort study. Lancet, 377, 147-52.

BEHR, M. A., HOPEWELL, P. C., PAZ, E. A., KAWAMURA, L. M., SCHECTER, G. F. & SMALL, P. M. 1998. Predictive value of contact investigation for identifying recent transmission of Mycobacterium tuberculosis. Am J Respir Crit Care Med, 158, 465-9.

BEYERS, N., GIE, R. P., SCHAAF, H. S., VAN ZYL, S., TALENT, J. M., NEL, E. D. & DONALD, P. R. 1997. A prospective evaluation of children under the age of 5 years living in the same household as adults with recently diagnosed pulmonary tuberculosis. Int J Tuberc Lung Dis, 1, 38-43.

KRITSKI, A. L., MARQUES, M. J., RABAHI, M. F., VIEIRA, M. A., WERNECK-BARROSO, E., CARVALHO, C. E., ANDRADE GDE, N., BRAVO-DE-SOUZA, R., ANDRADE, L. M., GONTIJO, P. P. & RILEY, L. W. 1996. Transmission of tuberculosis to close contacts of patients with multidrug-resistant tuberculosis. Am J Respir Crit Care Med, 153, 331-5.

KUABAN, C., KOULLA-SHIRO, S., LEKAMA ASSIENE, T. & HAGBE, P. 1996. [Tuberculosis screening of patient contacts in 1993 and 1994 in Yaounde, Cameroon]. Med Trop (Mars), 56, 156-8.

MARKS, S. M., TAYLOR, Z., QUALLS, N. L., SHRESTHA-KUWAHARA, R. J., WILCE, M. A. & NGUYEN, C. H. 2000. Outcomes of contact investigations of infectious tuberculosis patients. Am J Respir Crit Care Med, 162, 2033-8.

MORRISON, J., PAI, M. & HOPEWELL, P. C. 2008. Tuberculosis and latent tuberculosis infection in close contacts of people with pulmonary tuberculosis in low-income and middle-income countries: a systematic review and meta-analysis. Lancet Infect Dis, 8, 359-68.

NGUYEN, T. H., ODERMATT, P., SLESAK, G. & BARENNES, H. 2009. Risk of latent tuberculosis infection in children living in households with tuberculosis patients: a cross sectional survey in remote northern Lao People's Democratic Republic. BMC Infect Dis, 9, 96.

NOERTJOJO, K., TAM, C. M., CHAN, S. L., TAN, J. & CHAN-YEUNG, M. 2002. Contact examination for tuberculosis in Hong Kong is useful. Int J Tuberc Lung Dis, 6, 19-24.

RAHAJOE, N. N., BASIR, D., MAKMURI & KARTASASMITA, C. B. 2008. Pedoman nasional tuberkulosis anak, Jakarta, UKK Respirologi PP IDAI.

SCHAAF, H. S., SHEAN, K. & DONALD, P. R. 2003. Culture confirmed multidrug resistant tuberculosis: diagnostic delay, clinical features, and outcome. Arch Dis Child, 88, 1106-11.

TOPLEY, J. M., MAHER, D. & MBEWE, L. N. 1996. Transmission of tuberculosis to contacts of sputum positive adults in Malawi. Arch Dis Child, 74, 140-3. 

Citrin Deficiency (Citrulinemia)

Citrin is the aspartate-glutamate carrier protein (AGC: aspartate-glutamate carrier) in the mitochondrial membrane that are important in the synthesis of urea, proteins, nucleotides and gluconeogenesis (Ngu et al., 2010). Citrin presence will allow the exchange of aspartate in the mitochondria with glutamate in the cytosol and a proton. This function is important in the transfer of nicotinamide adenine dinucleotide (NADH) to balance the mitochondria as part of the malate-aspartate shuttle. NADH generated by malate oxidized generate adenosine triphosphate (ATP) on the oxidative phosphorylation pathway. AGC-specific protein plays an important supplier of aspartate to argininosuccinate synthetase (ASS) in the cytosol and produce argininosuccinate in the urea cycle. 

Thus, the lack of specific AGC in the liver (Citrin) will make the urea cycle dysfunction and hyperammonemia occurs. (Komatsu et al., 2008, Fernandes, 2006, Rodwell, 2006)Citrin deficiency is an autosomal recessive genetic disease caused by mutations of the gene SLC25A13 (Vajro and Veropalumbo, 2010, Ngu et al., 2010, Fu et al., 2010). These disorders can be characterized by progressive liver disease that usually begins in adolescence with the end result of cirrhosis.  

Citrulinemia differentiated into two phenotypes, namely: 

a. Citrulinemia type I
 
Type I Citrulinemia also known as classical citrulinemia, usually appear several days after birth. In type I occurs due to mutations in genes encoding aspartate aminosuksinat synthetase, an enzyme that serves to change citrulin arginosuksinat with aspartic acid in the cytosol. Citrulin will accumulate outside the mitochondria so that the urea cycle is not running. Affected babies appear normal at birth but blood ammonia levels that will provide increased energy deficiency symptoms (lethargy), poor feeding, vomiting, seizures, and loss of consciousness. The situation is in some cases very severe and life-threatening. Mild type I citrulinemia types can develop into adults in later life. Some people with gene mutations that cause citrulinemia type I also can not show abnormalities due to the formation of the enzyme aspartate compensation aminosuksinat synthetase II (Thoene, 1993).

b. Citrulinemia type II

Citrulinemia type II is generally attacks the nervous system, disorders of consciousness, weakness, impaired meori, deviant behavior (agitation and hyperactivity), seizures. Citrulinemia type II occurs due to the gene encoding gengguan Citrin, aspartate glutamate carrier. Disturbances in these carriers causes a lot of aspartate in the mitochondria can not easily escape to the cytosol in exchange for glutamate sehinggan citulin can not be converted into aspartic acid enzyme arginosuksinat arginosuksinat although I normally synthetase. As a consequence is the buildup citrulin and the cessation of the urea cycle.  

In some cases, signs and symptoms seen in adults (adult onset) that can be life-threatening and can be triggered by several triggers such as infection, drugs, alcohol and called CTNL2 surgery. Abnormalities in children known as the Neonatal intrahepatic cholestasis Caused by Citrin Deficiency (NICCD) (Fu et al., 2010, Ohura et al., 2007, Tamamori et al., 2004, Takagi et al., 2006).
 
During infancy, some individuals with SLC25A13 gene revealed homozygous mutations with cholestatic liver disease intrahepatal, although the symptoms are temporary and self limiting in most cases. Activity of arginine succinate synthetase (ASS) in the liver is affected, but activity in other parts of the body is not affected even no mutation in the gene ASS. Definitive diagnosis is made possible by genetic analysis for several mutations. These disorders have a higher incidence in the population of East Asia as one of the commonest causes of hyperammonemia in adults. (Endo et al., 2004) 

Provision of arginine effective in treating hyperammonemia, however, the effects are temporary. Specific treatment has not been determined, and liver transplantation is needed for cases with liver failure. (Endo et al., 2004)Citrin deficiency especially NICCD should be aware in all children with prolonged intrahepatic cholestasis. Of the 47 children with neonatal cholestasis in the study of Ko et al in Korea, found 11 children with biliary atresia, 4 children with congenital TORCH infections, 2 children with the syndrome Allagile and 21 children is not known why. NICCD was diagnosed in 3 children (6%) (Ko et al., 2007).  

Initial evaluation of children with cholestasis including ultrasoundgrafi, duodenal aspiration and biopsy can mengeklusi percutaneous biliary atresia. Liver biopsy is also necessary to detect the presence of Allagile syndrome, Dubin Johnson syndrome and progressive familial intrahepatic cholestasis (PFIC). GGT levels of fun also helps because the low levels often found in cholestasis PFIC.  

Amino acid analysis is useful in screening metabolic abnormalities such as NICCD (Ko et al., 2007, Ngu et al., 2010).Differential diagnoses include CTLN2 argininosuksinic pyruvate carboxylase deficiency asiduria and which showed an increase in plasma and urine sitrulin. Hiperamonia strengthen urea.selain alleged defect in the cycle, the neonates with cholestasis have investigated the possibility of occurrence of galactosemia and other hyperbilirubinemia (Thong et al., 2010).

REFERENCES

ENDO, F., MATSUURA, T., YANAGITA, K. & MATSUDA, I. 2004. Clinical manifestations of inborn errors of the urea cycle and related metabolic disorders during childhood. J Nutr, 134, 1605S-1609S; discussion 1630S-1632S, 1667S-1672S.

FERNANDES, J. V. 2006. Disorder of the urea cycle and related enzymes. In: J, F., JM, S., GVD, B. & JH, W. (eds.) Inborn metabolic disease. 4th ed. Wurzburg: Spinger Medizin Verlag.

FU, H. Y., ZHANG, S. R., YU, H., WANG, X. H., ZHU, Q. R. & WANG, J. S. 2010. Most common SLC25A13 mutation in 400 Chinese infants with intrahepatic cholestasis. World J Gastroenterol, 16, 2278-82.

KO, J. S., SONG, J. H., PARK, S. S. & SEO, J. K. 2007. Neonatal intrahepatic cholestasis caused by citrin deficiency in Korean infants. J Korean Med Sci, 22, 952-6.

KOMATSU, M., YAZAKI, M., TANAKA, N., SANO, K., HASHIMOTO, E., TAKEI, Y., SONG, Y. Z., TANAKA, E., KIYOSAWA, K., SAHEKI, T., AOYAMA, T. & KOBAYASHI, K. 2008. Citrin deficiency as a cause of chronic liver disorder mimicking non-alcoholic fatty liver disease. J Hepatol, 49, 810-20.

NGU, H. L., ZABEDAH, M. Y. & KOBAYASHI, K. 2010. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) in three Malay children. Malays J Pathol, 32, 53-7.

OHURA, T., KOBAYASHI, K., TAZAWA, Y., ABUKAWA, D., SAKAMOTO, O., TSUCHIYA, S. & SAHEKI, T. 2007. Clinical pictures of 75 patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). J Inherit Metab Dis, 30, 139-44.

RODWELL, V. 2006. Katabolisme protein & nitrogen asam amino. In: RK, M., DK, G. & VW, R. (eds.) Biokimia Harper (Harper's illustated biochemistry) (edisi Bahasa Indonesia). 27 ed. Jakarta: Penerbit Buku KEdokteran.

TAKAGI, H., HAGIWARA, S., HASHIZUME, H., KANDA, D., SATO, K., SOHARA, N., KAKIZAKI, S., TAKAHASHI, H., MORI, M., KANEKO, H., OHWADA, S., USHIKAI, M., KOBAYASHI, K. & SAHEKI, T. 2006. Adult onset type II citrullinemia as a cause of non-alcoholic steatohepatitis. J Hepatol, 44, 236-9.

TAMAMORI, A., FUJIMOTO, A., OKANO, Y., KOBAYASHI, K., SAHEKI, T., TAGAMI, Y., TAKEI, H., SHIGEMATSU, Y., HATA, I., OZAKI, H., TOKUHARA, D., NISHIMURA, Y., YORIFUJI, T., IGARASHI, N., OHURA, T., SHIMIZU, T., INUI, K., SAKAI, N., ABUKAWA, D., MIYAKAWA, T., MATSUMORI, M., BAN, K., KANEKO, H. & YAMANO, T. 2004. Effects of citrin deficiency in the perinatal period: feasibility of newborn mass screening for citrin deficiency. Pediatr Res, 56, 608-14.

THOENE, J. G. 1993. Citrullinemia Type I.

THONG, M. K., BOEY, C. C., SHENG, J. S., USHIKAI, M. & KOBAYASHI, K. 2010. Neonatal intrahepatic cholestasis caused by citrin deficiency in two Malaysian siblings: outcome at one year of life. Singapore Med J, 51, e12-4.

VAJRO, P. & VEROPALUMBO, C. 2010. Citrin deficiency: learn more, and don't forget to add it to the list of neonatal cholestasis and the NASH trash bin. J Pediatr Gastroenterol Nutr, 50, 578-9.

ANTHRACYCLIN-INDUCED CARDIOMYOPATHY

ANTHRACYCLIN-INDUCED CARDIOMYOPATHY

Andi Cahyadi, dr.

Resident of Pediatric, School of Medicine, Airlangga University

Surabaya, Indonesia

Chemotherapy is a well-established therapeutic approach for several malignancies^1-3, but its clinical efficacy is often limited by its related cardiotoxicity, which leads to cardiomyopathy, possibly evolving into heart failure^{2 4 5}. Cardiotoxicity may compromise the clinical effectiveness of chemotherapy, affecting survival, quality of life and prognosis^{2 4 6}. Cardiomyopathy can occur years after completion of chemotherapy and it is important to recognize earlier, as complete recovery of cardiac function^{2 5-12}. Dilated cardiomyopathy is the most common form of cardiomyopathy, caused by idiopathic cardiomyopathy of above 60%, followed by familial cardiomyopathy, active myocarditis and other causes such as cardiotoxic agents (doxorubicin)^{2 13} The most common cardiotoxic agent is athracycline derivate, such as doxorubicin (adriamicin, ADR).

The increasing number of patients treated by chemotherapy and to the availability of new, more aggressive antineoplastic drugs (combination and progressively higher cumulative doses), the incidence of cardiotoxicity is continuously growing^{4 10}.  For all cancers incidence increases with increasing age, therefore, it may have concomitant risk factor for cardiac diseases^{2 4 14}. Within the first 30 years after diagnosis, 75% of childhood cancer survivors will suffer from a chronic health condition such as cardiovascular related¹⁴. Incidence of cardiotoxicity depends on different risk factors.^{5 15}

Anthracyclines remain among the most widely prescribed and effective anticancer agents.¹⁴ Unfortunately, life-threatening cardiotoxicities continue to compromise their usefulness¹⁶. Anthracyclines are incorporated in more than 50% of regimens in childhood cancer such as rhabdomyosarcoma protocol, contributing to the 75% overall survival rates^{1 14}.

The probability of developing congestive heart failure (CHF) at a cumulative doxorubicin (anthracycilne derivate) of 300 mg/M² was between 0.7- 3.4%, rose to 1.3-6.1% at dose of 450 mg/M², and rose steeply at higher doses.  The occurrence of CHF seems to be in the range of 1-5%, and asymptomatic decrease in left ventricular function is in the range of 5-20%². Toxicity can occur early within 1 year or late particularly among children². The mortality rate is 20-30% and cardiac failure begin 1-2 months after treatment though the interval can be as long as 2 years³.

Cardiac events associated with chemotherapy may consist of mild blood pressure changes, thrombosis, electrocardiographic (ECG) changes, arrhythmias, myocarditis, pericarditis, myocardial infarction, cardiomyopathy, cardiac failure (left ventricular failure), and CHF. The risk for such effects depends upon: cumulative dose, rate of drug administration, mediastinal radiation, advanced age or younger age, female gender, pre-existing heart disease and hypertension². Conversely, cardiotoxicity remains a major limitation in standard and high-dose chemo­therapy, strongly impacting the quality of life and the overall survival, regardless of the onco­logic prognosis⁴.

Differences between pediatric, adult, and elderly patients and the lack of uniformity in detecting and reporting cardiac events make such estimates even more difficult.¹⁶ To detect cardiac damage, the adopted diagnostic approach is the estimation of left ventricular ejection fraction by echocardiography. Noninvasive or systemic markers that can predict or track anthracycline cardiotoxicity are needed, both for clinical monitoring and as surrogate end in research. This approach shows early prediction of cardiomyopathy, when the possibilities of appropriate treatments could still improve the patient’s outcome.

Early onset chronic of cardiotoxic effect of antracycline could happen although drug monitoring has been done regularly. Identification of those patients at higher risk will be one key strategy to reduce the morbidity and mortality from cardiotoxicity using serial echocardiography. It is difficult to judge continued or discontinued antineoplastic drug while cardiomyopathy occurred. Long-term outcome should be taken into account because the incidence of cardiac abnormalities can still be progressive despite chemotherapy has been completed. It is important to consider that the approach of cardiologists to the definition of disease is quite different from that of the oncologists.

REFERENCES

1. Smith LA, Cornelius VR, Plummer CJ, Levitt G, Verrill M, Canney P, et al. Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials. BMC Cancer 2010;10:337.

2. Shakir DK, Rasul KI. Chemotherapy induced cardiomyopathy: pathogenesis, monitoring and management. J Clin Med Res 2009;1:8-12.

3. Sriskandan S, O'Brien ME, Smith IE, Collins P, Gore ME. Aggressive management of doxorubicin-induced cardiomyopathy associated with 'low' doses of doxorubicin. Postgrad Med J 1994;70(828):759-61.

4. Dolci A, Dominici R, Cardinale D, Sandri MT, Panteghini M. Biochemical markers for prediction of chemotherapy-induced cardiotoxicity: systematic review of the literature and recommendations for use. Am J Clin Pathol 2008;130(5):688-95.

5. Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf 2000;22(4):263-302.

6. Albini A, Pennesi G, Donatelli F, Cammarota R, De Flora S, Noonan DM. Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention. J Natl Cancer Inst 2010;102(1):14-25.

7. Bryant J, Picot J, Levitt G, Sullivan I, Baxter L, Clegg A. Cardioprotection against the toxic effects of anthracyclines given to children with cancer: a systematic review. Health Technol Assess 2007;11(27):iii, ix-x, 1-84.

8. Frishman WH, Sung HM, Yee HC, Liu LL, Keefe D, Einzig AI, et al. Cardiovascular toxicity with cancer chemotherapy. Curr Probl Cancer 1997;21(6):301-60.

9. Granger CB. Prediction and prevention of chemotherapy-induced cardiomyopathy: can it be done? Circulation 2006;114(23):2432-3.

10. Jensen BV. Cardiotoxic consequences of anthracycline-containing therapy in patients with breast cancer. Semin Oncol 2006;33(3 Suppl 8):S15-21.

11. Lipshultz SE, Sanders SP, Goorin AM, Krischer JP, Sallan SE, Colan SD. Monitoring for anthracycline cardiotoxicity. Pediatrics 1994;93(3):433-7.

12. Rahman AM, Yusuf SW, Ewer MS. Anthracycline-induced cardiotoxicity and the cardiac-sparing effect of liposomal formulation. Int J Nanomedicine 2007;2(4):567-83.

13. Park MK. Pediatric cardiology for practitioner. 5th ed. Ohiladelphia: Mosby Elsevier, 2008.

14. Franco VI, Henkel JM, Miller TL, Lipshultz SE. Cardiovascular effects in childhood cancer survivors treated with anthracyclines. Cardiol Res Pract 2011;2011:134679.

15. Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med 1998;339(13):900-5.

16. Gianni L, Herman EH, Lipshultz SE, Minotti G, Sarvazyan N, Sawyer DB. Anthracycline cardiotoxicity: from bench to bedside. J Clin Oncol 2008;26(22):3777-84.