Naresh Shanmugam - Academia.edu (original) (raw)

Papers by Naresh Shanmugam

Hepatobiliary & Pancreatic Diseases International, 2018

A 49-year-old Chinese man with treatment-naïve chronic hepatitis B presented with a one-week hist... more A 49-year-old Chinese man with treatment-naïve chronic hepatitis B presented with a one-week history of jaundice when admitted to our hospital. On admission, his bilirubin was 704 μmol/L, alanine aminotransferase 180 U/L, international normalized ratio 2.4, creatinine 140 μmol/L, and Model for End-stage Liver Disease (MELD) score 35. His serum HBV DNA was 64.7 IU/mL, and he was commenced on entecavir. Nonetheless, he developed acute-onchronic liver failure on day 28 with grade 2 hepatic encephalopathy and a MELD score of 40 (bilirubin 709 μmol/L, international normalized ratio 3.3, creatinine 181 μmol/L). During his admission, he developed bacteremia and spontaneous bacterial peritonitis (SBP). His blood culture was positive of enterococcus faecium and coagulase-negative staphylococcus and his peritoneal fluid culture was positive of coagulase-negative staphylococcus. This was further complicated by the development of type 1 hepatorenal syndrome. His initial condition was so poor that intensive care with inotrope was needed. At the time of preconditioning, the sepsis due to SBP was barely controlled after optimization. An emergency ABO-incompatible (ABOi) living donor liver transplant (LDLT) was planned, as there was no suitable liver donor compatible with his A positive blood group. His 29-yearold daughter with blood group AB positive was worked up as a living donor. The preoperative ABOi protocol was modified, as shown in Fig. 1. In brief, rituximab (375 mg/m 2) was given two weeks before liver transplant. Plasma exchange with fresh frozen plasma from donors with blood group AB positive was performed (totally 34 units of fresh frozen plasma). His anti-B immunoglobulin M and immunoglobulin G titers were brought down from 1:64 and 1:8 to 1:16 and 1:2, respectively. Mycophenolate mofetil (MMF) was given one week before LDLT. The dosage was adjusted according to the patient's preexisting infection and a total of 3 g was given preoperatively. Antimicrobial treatments including meropenem, vancomycin and anidulafungin were prescribed preoperatively as treatment for his SBP and sepsis, and postoperatively as prophylaxis.

Pediatric Blood & Cancer

Annals of Pediatric Gastroenterology & Hepatology

Journal of Multidisciplinary Healthcare, 2022

Alagille syndrome (ALGS) is an autosomal dominant disorder characterized by involvement of variou... more Alagille syndrome (ALGS) is an autosomal dominant disorder characterized by involvement of various organ systems. It predominantly affects the liver, skeleton, heart, kidneys, eyes and major blood vessels. With myriads of presentations across different age groups, ALGS is usually suspected in infants presenting with high gamma glutamyl transpeptidase cholestasis and/ or congenital heart disease. In children it may present with decompensated cirrhosis, intellectual disability or short stature, and in adults vascular events like stroke or ruptured berry aneurysm are more commonly noted. Liver transplantation (LT) is indicated in children with cholestasis progressing to cirrhosis with decompensation. Other indications for LT include intractable pruritus, recurrent fractures, hepatocellular carcinoma and disfiguring xanthomas. Due to an increased risk of renal impairment noted in ALGS, these patients would require optimized renal sparing immunosuppression in the post-transplant period. As the systemic manifestations of ALGS are protean and a wider spectrum is being increasingly elucidated, a multidisciplinary team needs to be involved in managing these patients. Moreover, many basic-science and clinical questions especially with regard to its presentation and management remain unanswered. The aim of this review is to provide updated insights into the management of the multi-system involvement of ALGS.

Pediatric Liver Intensive Care, 2018

Two major pulmonary complications of liver disease are hepatopulmonary syndrome and portopulmonar... more Two major pulmonary complications of liver disease are hepatopulmonary syndrome and portopulmonary hypertension.

Pediatric Liver Intensive Care, 2018

This chapter outlines diagnosis and management of hypoglycaemic and hyperammonaemic crisis in chi... more This chapter outlines diagnosis and management of hypoglycaemic and hyperammonaemic crisis in children.

Clinical Liver Disease, 2021

pediatricians on early diagnosis of common pediatric liver problems, and tertiary prevention by e... more pediatricians on early diagnosis of common pediatric liver problems, and tertiary prevention by early referral to dedicated tertiary liver hospitals would help in decreasing the disease load and improve the outcomes.

BJS Open, 2020

Background Outcomes of high-risk hepatoblastoma have been dismal, especially in resource-challeng... more Background Outcomes of high-risk hepatoblastoma have been dismal, especially in resource-challenged countries where access to chemotherapy and paediatric liver transplantation is limited for the underprivileged. This study aimed to assess the results of treatment of high-risk hepatoblastoma in a tertiary centre, including patients who had non-transplant surgical procedures in the form of extended resection. Methods A review of patients with high-risk hepatoblastoma treated between January 2012 and May 2018 was carried out. Perioperative data and long-term outcomes were analysed. Results Of 52 children with hepatoblastoma, 22 were considered to have high-risk hepatoblastoma (8 girls and 14 boys). The mean(s.d.) age at diagnosis was 35(20) months. Of these 22 children, five died without surgery. Of the remaining 17 who underwent surgery, six had a resection (4 right and 2 left trisectionectomies) and 11 underwent living-donor liver transplantation. Median follow-up was 48 (range 12–90...

BMC Gastroenterology, 2020

Background Crigler Najjar type 1 is a rare autosomal recessive condition caused by the absence of... more Background Crigler Najjar type 1 is a rare autosomal recessive condition caused by the absence of UDPGT enzyme due to mutations in the UGT1A1 gene. This enzyme is responsible for elimination of unconjugated bilirubin from the body by glucuronidation. Affected individuals are at risk for kernicterus and require lifelong phototherapy. Liver transplant is the only definitive treatment. Case presentation Here we report a case of a 6 month old Sudanese female infant with CN1 whose molecular analysis revealed a novel homozygous 22 base pair duplication (c.55_76dup) in the coding exon 1 of the UGT1A1 gene. This 22 bp duplication causes a frame shift leading to a premature stop codon. She underwent a successful liver transplant at 7 months of age and is doing well at 1 year follow-up. Conclusion This study shows that molecular diagnosis helps in precise diagnosis of CN1 and in prognosis, prompt medical intervention and appropriate therapy. This particular 22 bp duplication within the coding...

Liver Transplantation, 2018

Anesthesia & Analgesia, 2019

The use of general descriptive names, registered names, trademarks, service marks, etc. in this p... more The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.

Indian Journal of Pediatrics

Indian Journal of Gastroenterology, 2022

A 9-year-old female child diagnosed with progressive familial intrahepatic cholestasis (PFIC) typ... more A 9-year-old female child diagnosed with progressive familial intrahepatic cholestasis (PFIC) type 1 presented with severe itching from first year of life. Pruritus was most severe in the palms and soles, extensor surfaces of the extremities, and trunk. It was generalized, continuous without diurnal variation, and unresponsive tomultiple combinations of antipruritic medications, resulting in inability to concentrate or attend school and to sleep continuously at night. She did not have jaundice and her pediatric end-stage liver disease score was 8. The most prominent clinical finding was hyperpigmented, stubby, broad hands, feet, fingers, and toes due to lichenification and thickening of the skin (Fig. 1A, B). This characteristic appearance is due to persistent rubbing of extremities against each other and hard objects in the vicinity [1]. The prolonged duration of persistent itching causes hyperkeratosis and the deformity of the extremities. This is a good indicator of the intensity and duration of pruritus. She underwent liver transplantation (LT) with simultaneous internal biliary diversion, the indication for LT being intractable itching and poor quality of life [2]. Itching subsided completely one week after LT and skin changes started to resolve after one month. At 6-month follow-up, the extremity changes had significantly improved with decrease in skin thickness and change in the appearance of fingers and toes (Fig. 2A, B). In conclusion, cosmetic deformity of the extremities due to prolonged, persistent pruritus improves after LT.

Liver biopsy (LB) is usually performed percutaneously, but in special situations, transjugular (T... more Liver biopsy (LB) is usually performed percutaneously, but in special situations, transjugular (TJ) approach, laparoscopic approach or even laparotomy might be required. Ultrasound-guided LB is the method of choice, particularly with “cutting needles”. In this chapter, only percutaneous LB is discussed.

Journal of Pediatric Genetics, 2020

Liver cirrhosis in infancy can be secondary to various etiologies such as biliary atresia, famili... more Liver cirrhosis in infancy can be secondary to various etiologies such as biliary atresia, familial cholestatic and metabolic disorders. Wolman's disease (WD) is a lysosomal storage disorder caused by the absence of lysosomal acid lipase enzyme activity and a significant association with infantile cholestasis and cirrhosis. We encountered an infant presenting with advanced cirrhosis and decompensation having splenomegaly for which the underlying etiology was found to be WD and the diagnostic clue came from abdominal X-ray showing bilateral adrenal calcifications. The diagnosis was confirmed by genetic analysis. The outcome was poor and died before 6 months of age without enzyme replacement therapy or hematopoietic stem cell transplantation.

Pediatric Liver Intensive Care, 2018

Liver plays an important role in coagulation. Apart from von Willebrand factor, all the other clo... more Liver plays an important role in coagulation. Apart from von Willebrand factor, all the other clotting factors are synthesized by the liver. Coagulopathy in liver disease is a reflection of synthetic liver failure. The normal coagulation cascade is outlined in Fig. 5.1. Always look for superimposed causes of coagulopathy such as vitamin K deficiency, infections, and renal failure.

Indian Journal of Pediatrics, 2021

To report the experience of liver transplantation (LT) for tyrosinemia type 1 (TT-1). Clinical da... more To report the experience of liver transplantation (LT) for tyrosinemia type 1 (TT-1). Clinical data of children with TT-1 who underwent living donor LT between July 2009 and May 2020 were retrospectively analyzed. Data included pre-LT nitisinone therapy, graft type, post-LT complications, HCC incidence, and graft/patient survival. Nine children were diagnosed with TT-1 at a median age of 12 mo (6–54 mo). Nitisinone was started in 6 patients at a median age of 15 mo (6–42 mo), but all had frequent interruption of therapy due to logistics with drug procurement including its cost. Median age at transplantation was 5 y (2–11 y). Explant liver showed HCC in 5 patients (55% of total cohort). The graft and patient survival are 100% with median follow-up of 58 mo (24–84 mo). LT is curative for TT-1 and excellent results can be obtained in experienced centers. This is especially favorable in countries with limited resources where the cost of medical therapy is highly prohibitive, with lifelong diet restrictions and unclear long-term risk of HCC.

Textbook of Liver Transplantation, 2022

World Journal of Transplantation, 2021

Metabolic liver diseases (MLD) are the second most common indication for liver transplantation (L... more Metabolic liver diseases (MLD) are the second most common indication for liver transplantation (LT) in children. This is based on the fact that the majority of enzymes involved in various metabolic pathways are present within the liver and LT can cure or at least control the disease manifestation. LT is also performed in metabolic disorders for end-stage liver disease, its sequelae including hepatocellular cancer. It is also performed for preventing metabolic crisis’, arresting progression of neurological dysfunction with a potential to reverse symptoms in some cases and for preventing damage to end organs like kidneys as in the case of primary hyperoxalosis and methyl malonic acidemia. Pathological findings in explant liver with patients with metabolic disease include unremarkable liver to steatosis, cholestasis, inflammation, variable amount of fibrosis, and cirrhosis. The outcome of LT in metabolic disorders is excellent except for patients with mitochondrial disorders where significant extrahepatic involvement leads to poor outcomes and hence considered a contraindication for LT. A major advantage of LT is that in the post-operative period most patients can discontinue the special formula which they were having prior to the transplant and this increases their well-being and improves growth parameters. Auxiliary partial orthotopic LT has been described for patients with noncirrhotic MLD where a segmental graft is implanted in an orthotopic position after partial resection of the native liver. The retained native liver can be the potential target for future gene therapy when it becomes a clinical reality.

Hepatobiliary & Pancreatic Diseases International, 2018

A 49-year-old Chinese man with treatment-naïve chronic hepatitis B presented with a one-week hist... more A 49-year-old Chinese man with treatment-naïve chronic hepatitis B presented with a one-week history of jaundice when admitted to our hospital. On admission, his bilirubin was 704 μmol/L, alanine aminotransferase 180 U/L, international normalized ratio 2.4, creatinine 140 μmol/L, and Model for End-stage Liver Disease (MELD) score 35. His serum HBV DNA was 64.7 IU/mL, and he was commenced on entecavir. Nonetheless, he developed acute-onchronic liver failure on day 28 with grade 2 hepatic encephalopathy and a MELD score of 40 (bilirubin 709 μmol/L, international normalized ratio 3.3, creatinine 181 μmol/L). During his admission, he developed bacteremia and spontaneous bacterial peritonitis (SBP). His blood culture was positive of enterococcus faecium and coagulase-negative staphylococcus and his peritoneal fluid culture was positive of coagulase-negative staphylococcus. This was further complicated by the development of type 1 hepatorenal syndrome. His initial condition was so poor that intensive care with inotrope was needed. At the time of preconditioning, the sepsis due to SBP was barely controlled after optimization. An emergency ABO-incompatible (ABOi) living donor liver transplant (LDLT) was planned, as there was no suitable liver donor compatible with his A positive blood group. His 29-yearold daughter with blood group AB positive was worked up as a living donor. The preoperative ABOi protocol was modified, as shown in Fig. 1. In brief, rituximab (375 mg/m 2) was given two weeks before liver transplant. Plasma exchange with fresh frozen plasma from donors with blood group AB positive was performed (totally 34 units of fresh frozen plasma). His anti-B immunoglobulin M and immunoglobulin G titers were brought down from 1:64 and 1:8 to 1:16 and 1:2, respectively. Mycophenolate mofetil (MMF) was given one week before LDLT. The dosage was adjusted according to the patient's preexisting infection and a total of 3 g was given preoperatively. Antimicrobial treatments including meropenem, vancomycin and anidulafungin were prescribed preoperatively as treatment for his SBP and sepsis, and postoperatively as prophylaxis.

Pediatric Blood & Cancer

Annals of Pediatric Gastroenterology & Hepatology

Journal of Multidisciplinary Healthcare, 2022

Alagille syndrome (ALGS) is an autosomal dominant disorder characterized by involvement of variou... more Alagille syndrome (ALGS) is an autosomal dominant disorder characterized by involvement of various organ systems. It predominantly affects the liver, skeleton, heart, kidneys, eyes and major blood vessels. With myriads of presentations across different age groups, ALGS is usually suspected in infants presenting with high gamma glutamyl transpeptidase cholestasis and/ or congenital heart disease. In children it may present with decompensated cirrhosis, intellectual disability or short stature, and in adults vascular events like stroke or ruptured berry aneurysm are more commonly noted. Liver transplantation (LT) is indicated in children with cholestasis progressing to cirrhosis with decompensation. Other indications for LT include intractable pruritus, recurrent fractures, hepatocellular carcinoma and disfiguring xanthomas. Due to an increased risk of renal impairment noted in ALGS, these patients would require optimized renal sparing immunosuppression in the post-transplant period. As the systemic manifestations of ALGS are protean and a wider spectrum is being increasingly elucidated, a multidisciplinary team needs to be involved in managing these patients. Moreover, many basic-science and clinical questions especially with regard to its presentation and management remain unanswered. The aim of this review is to provide updated insights into the management of the multi-system involvement of ALGS.

Pediatric Liver Intensive Care, 2018

Two major pulmonary complications of liver disease are hepatopulmonary syndrome and portopulmonar... more Two major pulmonary complications of liver disease are hepatopulmonary syndrome and portopulmonary hypertension.

Pediatric Liver Intensive Care, 2018

This chapter outlines diagnosis and management of hypoglycaemic and hyperammonaemic crisis in chi... more This chapter outlines diagnosis and management of hypoglycaemic and hyperammonaemic crisis in children.

Clinical Liver Disease, 2021

pediatricians on early diagnosis of common pediatric liver problems, and tertiary prevention by e... more pediatricians on early diagnosis of common pediatric liver problems, and tertiary prevention by early referral to dedicated tertiary liver hospitals would help in decreasing the disease load and improve the outcomes.

BJS Open, 2020

Background Outcomes of high-risk hepatoblastoma have been dismal, especially in resource-challeng... more Background Outcomes of high-risk hepatoblastoma have been dismal, especially in resource-challenged countries where access to chemotherapy and paediatric liver transplantation is limited for the underprivileged. This study aimed to assess the results of treatment of high-risk hepatoblastoma in a tertiary centre, including patients who had non-transplant surgical procedures in the form of extended resection. Methods A review of patients with high-risk hepatoblastoma treated between January 2012 and May 2018 was carried out. Perioperative data and long-term outcomes were analysed. Results Of 52 children with hepatoblastoma, 22 were considered to have high-risk hepatoblastoma (8 girls and 14 boys). The mean(s.d.) age at diagnosis was 35(20) months. Of these 22 children, five died without surgery. Of the remaining 17 who underwent surgery, six had a resection (4 right and 2 left trisectionectomies) and 11 underwent living-donor liver transplantation. Median follow-up was 48 (range 12–90...

BMC Gastroenterology, 2020

Background Crigler Najjar type 1 is a rare autosomal recessive condition caused by the absence of... more Background Crigler Najjar type 1 is a rare autosomal recessive condition caused by the absence of UDPGT enzyme due to mutations in the UGT1A1 gene. This enzyme is responsible for elimination of unconjugated bilirubin from the body by glucuronidation. Affected individuals are at risk for kernicterus and require lifelong phototherapy. Liver transplant is the only definitive treatment. Case presentation Here we report a case of a 6 month old Sudanese female infant with CN1 whose molecular analysis revealed a novel homozygous 22 base pair duplication (c.55_76dup) in the coding exon 1 of the UGT1A1 gene. This 22 bp duplication causes a frame shift leading to a premature stop codon. She underwent a successful liver transplant at 7 months of age and is doing well at 1 year follow-up. Conclusion This study shows that molecular diagnosis helps in precise diagnosis of CN1 and in prognosis, prompt medical intervention and appropriate therapy. This particular 22 bp duplication within the coding...

Liver Transplantation, 2018

Anesthesia & Analgesia, 2019

The use of general descriptive names, registered names, trademarks, service marks, etc. in this p... more The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.

Indian Journal of Pediatrics

Indian Journal of Gastroenterology, 2022

A 9-year-old female child diagnosed with progressive familial intrahepatic cholestasis (PFIC) typ... more A 9-year-old female child diagnosed with progressive familial intrahepatic cholestasis (PFIC) type 1 presented with severe itching from first year of life. Pruritus was most severe in the palms and soles, extensor surfaces of the extremities, and trunk. It was generalized, continuous without diurnal variation, and unresponsive tomultiple combinations of antipruritic medications, resulting in inability to concentrate or attend school and to sleep continuously at night. She did not have jaundice and her pediatric end-stage liver disease score was 8. The most prominent clinical finding was hyperpigmented, stubby, broad hands, feet, fingers, and toes due to lichenification and thickening of the skin (Fig. 1A, B). This characteristic appearance is due to persistent rubbing of extremities against each other and hard objects in the vicinity [1]. The prolonged duration of persistent itching causes hyperkeratosis and the deformity of the extremities. This is a good indicator of the intensity and duration of pruritus. She underwent liver transplantation (LT) with simultaneous internal biliary diversion, the indication for LT being intractable itching and poor quality of life [2]. Itching subsided completely one week after LT and skin changes started to resolve after one month. At 6-month follow-up, the extremity changes had significantly improved with decrease in skin thickness and change in the appearance of fingers and toes (Fig. 2A, B). In conclusion, cosmetic deformity of the extremities due to prolonged, persistent pruritus improves after LT.

Liver biopsy (LB) is usually performed percutaneously, but in special situations, transjugular (T... more Liver biopsy (LB) is usually performed percutaneously, but in special situations, transjugular (TJ) approach, laparoscopic approach or even laparotomy might be required. Ultrasound-guided LB is the method of choice, particularly with “cutting needles”. In this chapter, only percutaneous LB is discussed.

Journal of Pediatric Genetics, 2020

Liver cirrhosis in infancy can be secondary to various etiologies such as biliary atresia, famili... more Liver cirrhosis in infancy can be secondary to various etiologies such as biliary atresia, familial cholestatic and metabolic disorders. Wolman's disease (WD) is a lysosomal storage disorder caused by the absence of lysosomal acid lipase enzyme activity and a significant association with infantile cholestasis and cirrhosis. We encountered an infant presenting with advanced cirrhosis and decompensation having splenomegaly for which the underlying etiology was found to be WD and the diagnostic clue came from abdominal X-ray showing bilateral adrenal calcifications. The diagnosis was confirmed by genetic analysis. The outcome was poor and died before 6 months of age without enzyme replacement therapy or hematopoietic stem cell transplantation.

Pediatric Liver Intensive Care, 2018

Liver plays an important role in coagulation. Apart from von Willebrand factor, all the other clo... more Liver plays an important role in coagulation. Apart from von Willebrand factor, all the other clotting factors are synthesized by the liver. Coagulopathy in liver disease is a reflection of synthetic liver failure. The normal coagulation cascade is outlined in Fig. 5.1. Always look for superimposed causes of coagulopathy such as vitamin K deficiency, infections, and renal failure.

Indian Journal of Pediatrics, 2021

To report the experience of liver transplantation (LT) for tyrosinemia type 1 (TT-1). Clinical da... more To report the experience of liver transplantation (LT) for tyrosinemia type 1 (TT-1). Clinical data of children with TT-1 who underwent living donor LT between July 2009 and May 2020 were retrospectively analyzed. Data included pre-LT nitisinone therapy, graft type, post-LT complications, HCC incidence, and graft/patient survival. Nine children were diagnosed with TT-1 at a median age of 12 mo (6–54 mo). Nitisinone was started in 6 patients at a median age of 15 mo (6–42 mo), but all had frequent interruption of therapy due to logistics with drug procurement including its cost. Median age at transplantation was 5 y (2–11 y). Explant liver showed HCC in 5 patients (55% of total cohort). The graft and patient survival are 100% with median follow-up of 58 mo (24–84 mo). LT is curative for TT-1 and excellent results can be obtained in experienced centers. This is especially favorable in countries with limited resources where the cost of medical therapy is highly prohibitive, with lifelong diet restrictions and unclear long-term risk of HCC.

Textbook of Liver Transplantation, 2022

World Journal of Transplantation, 2021

Metabolic liver diseases (MLD) are the second most common indication for liver transplantation (L... more Metabolic liver diseases (MLD) are the second most common indication for liver transplantation (LT) in children. This is based on the fact that the majority of enzymes involved in various metabolic pathways are present within the liver and LT can cure or at least control the disease manifestation. LT is also performed in metabolic disorders for end-stage liver disease, its sequelae including hepatocellular cancer. It is also performed for preventing metabolic crisis’, arresting progression of neurological dysfunction with a potential to reverse symptoms in some cases and for preventing damage to end organs like kidneys as in the case of primary hyperoxalosis and methyl malonic acidemia. Pathological findings in explant liver with patients with metabolic disease include unremarkable liver to steatosis, cholestasis, inflammation, variable amount of fibrosis, and cirrhosis. The outcome of LT in metabolic disorders is excellent except for patients with mitochondrial disorders where significant extrahepatic involvement leads to poor outcomes and hence considered a contraindication for LT. A major advantage of LT is that in the post-operative period most patients can discontinue the special formula which they were having prior to the transplant and this increases their well-being and improves growth parameters. Auxiliary partial orthotopic LT has been described for patients with noncirrhotic MLD where a segmental graft is implanted in an orthotopic position after partial resection of the native liver. The retained native liver can be the potential target for future gene therapy when it becomes a clinical reality.