Chronic Hepatitis C Infection: Pathogenesis, Complications, and Unpredictable Anesthesia Outcomes
Nickul N. Shah, MD Candidate, and Samuel Wilson, MD
Shah NN, Willson S. Chronic hepatitis C infection: pathogenesis, complications, and unpredictable anesthesia outcomes. Consultant. 2016;56(1):41-45.
ABSTRACT: The risk of anesthesia is unpredictable in patients with underlying hepatitis C virus (HCV) infection. No definitive diagnostic measure is available to evaluate the severity of hepatic cell damage from chronic conditions or previous trauma, infections, or toxins. Moreover, limited data exist to guide clinical decision-making when quantifying the severity of cirrhosis in patients with underlying HCV infection and its relationship to the choice of anesthesia. It is imperative to consider the benefits and risks associated with the use of anesthetics during elective surgery in patients with underlying HCV infection. Awareness of these medications is important in order to prevent related intraoperative and postoperative adverse events and effects.
KEYWORDS: Sevoflurane, hepatitis C, hepatocellular toxicity, cellular necrosis, abdominal surgery
Published studies have found that exposure to general anesthesia during abdominal surgery may increase the risk of hepatorenal failure. Increased concern exists that anesthetics may interfere with various hepatic functions secondary to viral infection. Sevoflurane, however, is considered a safe choice of inhaled anesthetic in patients with liver disease. Compared with other halogenated inhaled anesthetics, sevoflurane has been reported to lessen the severity of decreased hepatic blood flow in that it is metabolized via the cytochrome P450 2E1 pathway and the heme oxygenase pathway. In patients with preexisting liver disease, low-flow sevoflurane has the potential to induce acute liver damage through other mechanisms. Limited data exist to guide clinical decision-making when quantifying the severity of cirrhosis in patients with hepatitis C and its relationship to anesthesia choice.
A 53-year-old man with a history of hypertension and hepatitis C infection underwent elective hernia repair. He had been referred to the surgical clinic because of intermittent abdominal discomfort secondary to a 10- × 8-cm ventral hernia. During the clinic visit, the patient reported that he had a history of hepatitis C virus (HCV) infection, but he was otherwise asymptomatic, and no physical stigmata of cirrhosis were evident.
The patient stated that the ventral hernia had been the result of abdominal trauma in some 30 years previously requiring laparotomy. Aside from occasional discomfort while lying flat, the remainder of findings of the review of systems was negative. He had had no other surgery other than the posttraumatic laparotomy, and he had no allergies or organ dysfunction. His hypertension was being controlled with furosemide and spironolactone. He had never been symptomatic for or treated for HCV.
After discussing the risks of, benefits of, and alternatives to hernia repair, he agreed to and was scheduled for operative repair. Preoperative testing and laboratory tests were ordered according to best practice guidelines. Given this patient’s history of HCV, a complete metabolic panel and coagulation panel were ordered, the results of which are shown in the accompanying Table. Upon admission, the patient had a decreased platelet count (98 × 103/µL) and a low hematocrit (35.7%). Liver aminotransferases and alkaline phosphatase (ALP) were elevated, and the prothrombin time/international normalized ratio also was slightly elevated. Serum electrolytes and kidney function tests findings were within normal ranges.
Preoperative sedation with midazolam, 2 mg, was administered. Initially during the operation, it took approximately 30 minutes for lysis of adhesions due to the patient’s hernia. Attention was focused on the hernia repair; therefore, no effort was made to lyse adhesions that did not interfere with the procedure, or to explore the rest of the abdomen. However, a portion of the liver that was readily visible had a hard and nodular appearance, consistent with cirrhosis. During the separation of components, the cutaneous flaps were not excessive, and the external oblique release provided enough length to achieve a tension-free fascia approximation. A lightweight polypropylene mesh was placed in the retrorectus space and was fixated with transfascial absorbable sutures. The patient tolerated the procedure without any immediate complications.
Intravenous fentanyl 150 µg, propofol 200 mg, rocuronium 50 mg, and ketamine 20 mg were administered anesthesia along with induction of anesthesia. Sevoflurane with end-tidal concentration of 1.6% volume with oxygen and air (fresh gas flow 2 L/min) was used for maintenance of general anesthesia. Anesthesia lasted 4 hours. Throughout the procedure, the patient’s heart rate, blood pressure, and temperature remained within normal limits. Oxygen saturation stayed above 98%. Estimated blood loss was 700 mL. Postoperatively, the patient was extubated in the operating room, was transported to the recovery room, and had a normal arousal timeframe. After recovery in the postacute care unit, the patient was transferred to the general floor. Pain was controlled with hydromorphone.
Two days after surgery, the patient became tachycardic, tachypneic, and hypotensive. His abdominal wound was intact, but his abdomen was distended, and dressings were saturated with blood. After stat laboratory tests (Table) and imaging, the patient was transferred to the intensive care unit (ICU) due to impending shock. Laboratory study results showed metabolic acidosis with increased anion gap due to lactic acidosis. Despite hemodynamic support, he had experienced cardiac arrest and required cardiopulmonary resuscitation. Once the return of spontaneous circulation, achieved after 20 minutes, emergent hemodialysis was required for metabolic derangements.
On postoperative day 3, the patient continued to be hemodynamically unstable and was in hypovolemic shock. Acute blood loss despite administration of blood products suggested disseminated intravascular coagulation (DIC), and low urine output suggested acute renal failure. Increased abdominal distention and high bladder pressure were concerning for abdominal compartment syndrome, which led to emergent decompressive laparotomy. Intraoperatively, there was no major source of bleeding, the liver was cirrhotic but without injury, and there was no evidence of ischemic bowel.
The patient was taken to the ICU for further care, where he required continued multiple pressor support, hemodialysis, and blood products. Despite all efforts and aggressive measures, the patient became hemodynamically unstable due to multiorgan failure and experienced cardiac arrest twice. After attempts to resuscitate the patient failed, the decision was made to withdraw all lifesaving measures, and the patient died. Pending autopsy findings, the patient’s cause of death was multisystem organ failure in the setting of hepatic dysfunction and DIC.
An autopsy was performed at the patient’s family’s request. Findings revealed no direct anatomic cause of death; however, the patient was noted to have had severe macronodular cirrhosis, diffuse pulmonary edema, and cardiomyopathy.
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Infection with HCV, a member of the Flaviviridae family of viruses with 6 known genotypes,1 is a major public health problem and is the leading cause of decompensated chronic liver disease. Much controversy surrounds the natural history of HCV infection. The rate of chronic HCV infection is affected by a person’s age, gender, race, and viral immune response. Approximately 75% to 85% of HCV-infected persons will progress to chronic HCV infection and are at risk for the development of extrahepatic manifestations, compensated and decompensated cirrhosis, and hepatocellular carcinoma (HCC). The rate of progression to cirrhosis is highly variable and is influenced by several factors, including the amount of alcohol consumption, age at initial HCV infection, degree of inflammation and fibrosis on liver biopsy, the presence of HIV and/or hepatitis B virus coinfection, and the presence other comorbid conditions.2
The major risk factors for acquisition of HCV are associated with IV drug use, transfusion of blood products, tattoos, sexual transmission, or occupation risk.3,4 This knowledge has allowed researchers to identify the many factors related to acquiring this condition and, more importantly, the many human conditions that may alter the rate of progression in some patients. Given the known HCV genotypes and the many more subtypes, the reaction and rate of progression has considerable variability.
HCV elicits a weak T cell response in chronic infection. There is a progressive loss in the strength of reaction toward HCV antigens during chronic infection. Impaired CD8 cell response is the consequence of dysfunctional T cells rather than persistent infection.5,6 Viral persistence includes the suppressive effect of HCV antigens on the innate and adaptive immune systems.1 Progression to persistent infection and immunologic mechanisms of liver injury are a consequence of complex interactions among the virus and host.1,7
Risk factors for a significantly higher rate of liver complications include age (> 50 years), blood transfusion, HCV genotypes 1 and 4, fibrosis, and cirrhosis.8 Additional risk factors include abnormalities in bilirubin (> 40 µmol/L), albumin, and prothrombin time; thrombocytopenia (< 50,000 cells/dL); and detection of α1-fetoprotein (> 20 µg/L).9 Patients with advanced hepatic fibrosis or cirrhosis are at higher risk of developing liver complications from chronic hepatitis C. Infected individuals are predominantly asymptomatic but can progress to end-stage liver disease, liver cirrhosis, portal hypertension, HCC, and premature death. The rate of fibrotic progression in chronic hepatitis C is highly variable, and the natural history extends over decades.10 Factors that influence the rate of progression include age at diagnosis, male gender, and HCV genotype; alcohol consumption appears to be one of the most influential factors driving fibrosis progression in patients with chronic HCV infection. Convincing evidence exists that higher levels of alcohol consumption contribute to the development of progressive liver disease.11-17 Personal, viral, and disease-related factors that influence the development of liver complications remain poorly documented.9,10,18
Approximately 80% of those who become infected with HCV fail to clear the virus and progress to chronic infection, with poorly defined outcomes.19 Some people recover, some remain viremic without overt liver damage, some remain static with elevated aspartate aminotransferase (AST) levels without symptoms, and some progress to fibrosis and cirrhosis or develop liver failure or HCC.20 The course of the disease spans 20 to 40 years before the outcome is reached, with a close association between the development of cirrhosis and HCC.
Only approximately 10% of patients with hepatic cirrhosis develop signs and symptoms of it.1 These indicators can include ascites (abdominal distention, shifting dullness, and fluid confirmed by paracentesis or abdominal imaging), variceal bleeding, spontaneous bacterial peritonitis (> 500 white blood cells/mL, > 250 polymorphonuclear cells/mL, positive culture), hepatic hydrothorax (right-sided pleural effusion), and hepatic encephalopathy (asterixis, or flapping tremor).21 Management requires aggressive diuresis, pleural taps, and immediate consideration for liver transplantation based on the Model for End-Stage Liver Disease (MELD).22
Therapy for hepatitis C is indicated for patients 18 to 60 years of age with persistently abnormal alanine aminotransferase (ALT) levels, HCV RNA in serum, or liver biopsy showing chronic hepatitis with fibrosis or inflammation.23 The goal is to prevent complications and death from HCV infection. The normalization of serum ALT, undetected HCV RNA by sensitive polymerase chain reaction (PCR) analysis, and nondetectable fibrosis on histology measure short-term outcomes.24
It is important to recognize virologic responses with a reduced viral load and decreased symptoms; this is defined as the absence of HCV RNA from serum by sensitive PCR assay 24 weeks after cessation of therapy.1 Rapid virologic response is defined as undetectable HCV RNA at 4 weeks of treatment, with a lower limit of detection of 50 IU/mL. Early virologic response is the most accurate predictor of not achieving sustained viral response, with an absence of serum HCV RNA at 12 weeks.24,25
Despite management, HCV RNA levels do not change, and relapses occur soon after cessation of treatment. The therapeutic regimen includes interferon alfa given subcutaneously in a dose of 3 million units 3 times weekly for 12 months.1 Modifications include a combination therapy with interferon alfa and ribavirin.25-27 Patients receiving interferon alfa alone or in combination had low to nondetectable levels of HCV RNA 6 months after therapy (indicating sustained virologic response).24,26-28 Residual viral indexes maintain persistent humoral and cellular immunologic responses once the therapy reduces viral load.4,27 An additional option is long-term continuous interferon or ribavirin therapy in patients with extrahepatic manifestations, those with marked fibrosis on liver biopsy, or those at high risk for HCC.3
Chronic HCV infection is the leading indication for liver transplantation in the US population.29 Extrahepatic manifestations can occur during chronic HCV infection or cirrhosis, but HCC appears to develop only after cirrhosis is established. Research is ongoing to determine the histologic, biochemical, genetic, and demographic markers that may further predict the outcome of HCV infections. Criteria for liver transplant24,29 include signs of hepatic decompensation, encephalopathy, variceal bleed, and a MELD score greater than 10. Immunocompromised patients have a higher recurrence rate and a lower survival rate. Therefore, the use of interferon-based antiviral therapy currently has a variable response rate in such patients.1,24
This variable response may require liver biopsies to monitor progressive fibrosis and initiate treatment.24,30,31
Preoperatively, it is important to evaluate patients for liver disease, since it has been associated with increased postoperative complications and mortality.32 With the patient’s history of hepatitis C, the next step was to assess the severity of liver dysfunction. Our patient had confirmatory HCV testing with a high viral load using quantitative HCV RNA by PCR (1,678,859 IU/mL). Additionally, he had never been treated for HCV with pegylated interferon or ribavirin, which aims to slow the progression of fibrosis and prevent the development of cirrhosis.33 Preoperative laboratory evaluation showed a platelet count of less than 140,000 and an AST/ALT ratio greater than or equal to 1, which are highly suggestive of cirrhosis in patients with chronic HCV.33
Using noninvasive methods, the Child-Turcotte-Pugh (CTP) and the MELD scoring systems can be used to quantify the severity of hepatic dysfunction. The CTP score predicts severity of liver dysfunction and postoperative morbidity and mortality risk. Preoperatively, our patient was in CTP class A, associated with a 10% surgical mortality rate. The MELD score can be used to predict 30-day mortality postoperatively in patients with cirrhosis by estimating the severity of liver disease. We found that our patient had a MELD score of 11, predicting a 10.3% 30-day mortality rate.34,35
Although no specific guidelines have been widely established, several considerations have been suggested by the American College of Gastroenterology, which include contraindications to elective surgery in patients with CTP class C with a high MELD score. In addition, using the American Society of Anesthesiologists (ASA) Physical Status Classification System, which is widely used to assess preoperative health, a categorization of class V (moribund patients not expected to survive 24 hours without an operation) represents a
severe contraindication to elective surgery. Moreover, it might be prudent not to consider elective surgery in patients with underlying HCV infection who are in ASA class III (systemic disease with substantive functional limitations) and a MELD score of 10. Overall, however, acute hepatitis, severe coagulopathy, or severe extrahepatic manifestations of liver disease36 are all contraindications for proceeding with elective surgery. Management of ascites, coagulopathy, and encephalopathy is required before proceeding with surgery. In general, for asymptomatic patients with mildly elevated aminotransferase levels and a normal total bilirubin level, cancellation of surgery is rarely needed.34
Sevoflurane may have contributed to this patient’s death through several mechanisms. Since its introduction in 1990, sevoflurane has been established in clinical practice and is considered safer than other halogenated anesthetics. Nevertheless, hepatic injuries have been reported over the years.37 While many factors contributed to the patient’s hepatic injury, such as chronic hepatitis, he was hemodynamically stable preoperatively and intraoperatively. However, over time, this patient developed hypercoagulability that was unresponsive to supportive therapy, and he eventually died. Postoperatively, liver enzymes were dramatically elevated, and it became clear that exposure to sevoflurane contributed to, if not was the primary factor in, the acute liver failure in the postoperative period, with HCV infection being responsible for already compromised liver function.
Clinicians should be aware that using sevoflurane in a patient with HCV infection, where the patient has not received immune suppression therapy, and where the condition shows clear evidence of progression with a compromise of liver function, the possibility of total liver failure should be a part of the discussion of informed consent. Sevoflurane is metabolized to hexafluoroisopropanol, inorganic fluoride, and formaldehyde,38 which are eliminated in the urine. Sevoflurane’s metabolite, Compound A, an alkane, is metabolized by human cytochrome P450 2E1 and is responsible for anesthesia-induced hepatotoxicity.39 Sevoflurane also may affect the metabolic enzyme heme oxygenase within Kupffer cells of the liver.39 Free radical release also occurs through tissue interaction with sevoflurane, with the induction of cytochrome P450 2E1 metabolism.39
Variable liver function abnormalities have been studied in patients under sevoflurane anesthesia. In recent studies,40,41 hepatic function tests were conducted during preoperative and postoperative days 1 and 3 in which AST and ALP were shown to increase. Hepatic necrosis, coagulopathies, and hyperbilirubinemia occur secondary to drug-induced sevoflurane.42 Additionally, patients with an underlying HCV infection and exposure to sevoflurane have a risk of hepatic necrosis with life-threatening consequences.39 Even though the patient in the case described here received a low flow rate administration of 2 L/min, anesthesia providers should be aware of the accumulation of sevoflurane in the setting of renal and hepatic toxicity.43
Nickul N. Shah, MD candidate, will graduate in June 2016 from the American University of Antigua College of Medicine in Antigua.
Samuel Wilson, MD, is an anesthesiologist and critical care physician at Northside Medical Center in Youngstown, Ohio.
- Liang TJ, Rehermann B, Seeff LB, Hoofnagle JH. Pathogenesis, natural history, treatment, and prevention of hepatitis C. Ann Intern Med. 2000;132(4):296-305.
- Chen SL, Morgan TR. The Natural history of hepatitis C virus (HCV) infection. Int J Med Sci. 2006;3(2):47-52.
- Tong MJ, El-Farra NS, Reikes AR, Co RL. Clinical outcomes after transfusion-associated hepatitis C. N Engl J Med. 1995;332(22):1463-1466.
- Gordon SC, Bayati N, Silverman A. Clinical outcome of hepatitis C as a function of mode of transmission. Hepatology. 1998;28(2):562-567.
- Cox AL, Mosbruger T, Lauer GM, Pardoll D, Thomas DL, Ray SC. Comprehensive analyses of CD8+ T cell responses during longitudinal study of acute human hepatitis C. Hepatology. 2005;42(1):104-112.
- Cabrera R, Tu Z, Xu Y, et al. An immunomodulatory rule for CD4+CD25+ regulatory T lymphocytes in hepatitis C virus infection. Hepatology. 2004;40(5):1062-1071.
- Nishimura T, Ohta A. A critical role for antigen-specific Th1 cells in acute liver injury in mice.J Immunol. 1999;162(11):6503-6509.
- Spangenberg HC, Viazov S, Kersting N, et al. Intrahepatic CD8+ T-cell failure during chronic hepatitis C virus infection. Hepatology. 2005;42(4):828-837.
- Khan MH, Farrell GC, Byth K, et al. Which patients with hepatitis C develop liver complications? Hepatology. 2000;31(2):513-520.
- Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997;349(9055):825-832.
- Wiley TE, McCarthy M, Breidi L, McCarthy M, Layden TJ. Impact of alcohol on the histological and clinical progression of hepatitis C infection. Hepatology. 1998;28(3):805-809.
- Noda K, Yoshihara H, Suzuki K, et al. Progression of type C chronic hepatitis to liver cirrhosis and hepatocellular carcinoma—its relationship to alcohol drinking and the age of transfusion. Alcohol Clin Exp Res. 1996;20(1 suppl):95A-100A.
- Ostapowicz G, Watson KJ, Locarnini SA, Desmond PV. Role of alcohol in the progression of liver disease caused by hepatitis C virus infection. Hepatology. 1998;27(6):1730-1735.
- Peters MG, Terrault NA. Alcohol use and hepatitis C. Hepatology. 2002;36(5 suppl 1):S220-S225.
- Pessione F, Degos F, Marcellin P, et al. Effect of alcohol consumption on serum hepatitis C virus RNA and histological lesions in chronic hepatitis C. Hepatology. 1998;27(6):1717-1722.
- Corrao G, Aricò S. Independent and combined action of hepatitis C virus infection and alcohol consumption on the risk of symptomatic liver cirrhosis. Hepatology. 1998;27(4):914-919.
- Harris DR, Gonin R, Alter HJ, et al. The relationship of acute transfusion-associated hepatitis to the development of cirrhosis in the presence of alcohol abuse. Ann Intern Med. 2001;134(2):120-124.
- Harris DR, Gonin R, Alter HJ, Wright EC, et al; National Heart, Lung, and Blood Institute Study Group. The relationship of acute transfusion-associated hepatitis to the development of cirrhosis in the presence of alcohol abuse. Ann Intern Med. 2001;134(2):120-124.
- Gut J. Molecular basis of halothane hepatitis. Arch Toxicol Suppl. 1998;20:3-17.
- Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144(10):705-714.
- Afdhal NH. The natural history of hepatitis C. Semin Liver Dis. 2004;24(suppl 2):3-8.
- Murillas J, Rimola A, Laguno M, et al; ESLD-HIV Working Group Investigators. The model for end-stage liver disease score is the best prognostic factor in human immunodeficiency virus 1-infected patients with end-stage liver disease: a prospective cohort study. Liver Transpl. 2009;15(9):1133-1141.
- National Institutes of Health Consensus Development Conference Panel statement: management of hepatitis C. Hepatology. 1997;26(3 suppl 1):2S-10S.
- Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49(4):1335-1374.
- Yu J-W, Wang G-Q, Sun L-J, Li X-G, Li S-C. Predictive value of rapid virological response and early virological response on sustained virological response in HCV patients treated with pegylated interferon α-2a and ribavirin. J Gastroenterol Hepatol. 2007;22(6):832-836.
- Yu M-L, Dai C-Y, Lee L-P, et al. A 24-week course of high-dose interferon-alpha plus ribavirin for Taiwanese chronic hepatitis C patients with persistently normal or near-normal alanine aminotransferase levels. Liver Int. 2006;26(10):1187-1195.
- Jacobson IM, Ahmed F, Russo MW, et al. Interferon alpha-2b and ribavirin for patients with chronic hepatitis C and normal ALT. Am J Gastroenterol. 2004;99(9):1700-1705.
- Zeuzem S, Diago M, Gane E, et al; PEGASYS Study NR16071 Investigator Group. Peginterferon alfa-2a (40 kilodaltons) and ribavirin in patients with chronic hepatitis C and normal aminotransferase levels. Gastroenterology. 2004;127(6):1724-1732.
- Alter H. Viral hepatitis. Hepatology. 2006;43(2 suppl):S230-S234.
- Neumann UP, Berg T, Bahra M, et al. Fibrosis progression after liver transplantation in patients with recurrent hepatitis C. J Hepatol. 2004;41(5):830-836.
- Yilmaz N, Shiffman ML, Stravitz RT, et al. A prospective evaluation of fibrosis progression in patients with recurrent hepatitis C virus following liver transplantation. Liver Transpl. 2007;13(7):975-983.
- Nicoll A. Surgical risk in patients with cirrhosis. J Gastroenterol Hepatol. 2012;27(10):1569-1575.
- Iacobellis A, Mangia A, Leandro G, et al. External validation of biochemical indices for noninvasive evaluation of liver fibrosis in HCV chronic hepatitis. Am J Gastroenterol. 2005;100(4):868-873.
- Hanje AJ, Patel T. Preoperative evaluation of patients with liver disease. Nat Clin Pract Gastroenterol Hepatol. 2007;4(5);266-276.
- Teh SH, Nagorney DM, Stevens SR, et al. Risk factors for mortality after surgery in patients with cirrhosis. Gastroenterology. 2007;132(4):1261-1269.
- Keegan MT, Plevak DJ. Preoperative assessment of the patient with liver disease. Am J Gastroenterol. 2005;100:2116-2127.
- Alotaibi WM. Severe hepatic dysfunction after sevoflurane exposure. Saudi Med J. 2008;29(9):1344-1346.
- Martin JL. Volatile anesthetics and liver injury: a clinical update or what every anesthesiologist should know. Can J Anaesth. 2005;52(2):125-129.
- Hoetzel A, Leitz D, Schmidt R, et al. Mechanism of hepatic heme oxygenase-1 induction by isoflurane. Anesthesiology. 2006;104(1):101-109.
- Kim JW, Kim JD, Yu SB, Ryu SJ. Comparison of hepatic and renal function between inhalation anesthesia with sevoflurane and remifentanil and total intravenous anesthesia with propofol and remifentanil for thyroidectomy. Korean J Anesthesiol. 2013;64(2):112-116.
- Obata R, Bito H, Ohmura M, et al. The effects of prolonged low-flow sevoflurane anesthesia on renal and hepatic function. Anesth Analg. 2000;91(5):1262-1268.
- Singhal S, Gray T, Guzman G, Verma A, Anand K. Sevoflurane hepatotoxicity: a case report of sevoflurane hepatic necrosis and review of the literature. Am J Ther. 2010;17(2):219-222.
- Liu S-j, Li Y, Sun B, et al. Sofnolime with different water content causes different effects in two sevoflurane inhalational induction techniques with respect to the output of compound-A. Int J Med Sci. 2012;9(6):435-440.