Evaluation of Liver Disease in older children and adolescents Dr Juliana Muiva-Gitobu KPA ASC, Mombasa, Kenya April 2019

Outline Case presentation Liver functions Overview of liver disease in infancy and older children Specific illnesses reviewed Conclusion

Patient I.A. 15 year with history of progressive and generalized body weakness and swelling of the lower limbs and abdomen over the last 1 year O/E: FGC. Oedema+, mild pallor, abdominal distension with ascites and hepatomegally What are his possible differential diagnoses? What workup would you like to do?

Liver Functions Revision Uptake and processing of nutrients from the intestinal tract Synthesis and biotransformation of proteins, carbohydrates and lipids Excretion of bile and hydrophobic compounds Regulation of energy metabolism Endocrine functions Imunological Drug metabolism Fluid balance

Liver Disease in Infants Anatomic : Biliary atresia, Choledochal cyst Infectious : TORCHes Metabolic : galactosemia Autoimmune : neonatal sclerosing cholangitis Vascular : CCF, constrictive pericarditis Toxic/Drug induced : PNALD

Spectrum of Liver Disease in older children Anatomic Infectious Metabolic Autoimmune Vascular Toxic/Drug induced

Anatomic Intra-Hepatic Bile Duct diseases (Ductal Plate Malformation): Congenital Hepatic Fibrosis Caroli’s Disease and Syndrome Autosomal Dominant Polycystic Kidney Disease Extra-Hepatic Bile Duct Diseases Choledochal Cysts

Non Alcoholic Liver Disease Infectious Metabolic Hepatitis B Hepatitis A Wilson’s Disease Hemochromatosis Non Alcoholic Liver Disease

Autoimmune Hepatitis ASC Haemangioma Portal Hypertension Vascular disorders Autoimmune Liver Disease Autoimmune Hepatitis ASC Haemangioma Portal Hypertension

Toxic & Drug Induced Liver Disease Toxic e.g. Aflatoxin Drug induced Dose Dependent Idiosyncratic

Disorders of Ductal Plate Malformation

Disorders of Ductal Plate Malformation Can present with hepatomegally or can be incidental finding Features of portal hypertension Liver Functions may/may not be deranged Radiology important: Ultrasound, MRI Management guided by management of underlying disease and associated complications e.g renal disease Surgical intervention esp for choledochal cyst, prevent biliary cirrhosis

Hepatitis B Persistent HBsAg positive >6/12 >360 million persons infected worldwide Majority of childhood infections in vertical or horizontal transmission Risk of chronicity 90% newborn 20-30% <5 years <5% adults Majority are asymptomatic. Some with malaise, anorexia, abdominal discomfort, then jaundice. 1% of acute infections may have severe presentation

Stages of Hepatitis B infection

Treatment Strategies Hepatitis B

Hepatitis A RNA virus, fecal-oral transmission Majority of infections asymptomatic, up to 1.5 million cases annually Clinically presents with anorexia, nausea, malaise, fever, abdominal pain, diarrhoea and vomiting 1% with severe presentation, 0.2-0.4% mortality, especially with fulminant hepatic failure. Relapses possible

Hepatitis A Diagnosis: Ultrasound and liver biopsy not routine Clinical features ALT> x10 ULN, or 400 ELISA anti-HAV IgM Ultrasound and liver biopsy not routine

Wilson’s disease Copper: essential co-factor for several proteins; useful in neurological signalling and RBC formation. Wilson’s disease: impaired excretion of Cu →Accumulation of Cu in hepatocytes, with eventual spillover to other systems Defective gene ATP7B →defective protein →Decreased Cu excretion & defective caeruplasmin formation

Clinical features

Diagnosis of Wilson’s Disease

Treatment of Wilson’s Disease Reduce copper intake Increase copper excretion: D-penicillamine, Trientine Reduce copper absorption: Zinc acetate Liver Transplantation

Autoimmune Hepatitis Disease characterised by Histologically:Dense mononuclear cell infiltrate in portal tracts Serology: Hypergammaglobulinemia, Autoantibodies Chemically: elevated transaminases 3 Types autoimmune hepatitis autoimmune sclerosing cholangitis  de novo autoimmune hepatitis after liver transplantation

Clinical Features Affects predominantly females Divided into 2 types based on antibody profiles Type 1  positive for ANA and/or anti-smooth muscle antibodies Type 2  positive for anti-Liver/Kidney microsomal antibody type 1 median age of 10 years in type 1 and 7.4 years in type 2 Can present with fulminant hepatic failure in 10%, Portal hypertension +/- GI bleeding, or can be asymptomatic Type 2 associated with other AI disorders e.g. IDDM, Thyroiditis and IBD

Diagnosis LFTs: Serology: raised AST and ALT normal or mildly raised GGT and ALP Variable bilirubin Low Albumin abnormal INR Serology: ANA, ASM, ALKM titres of 1/20 for ANA/SMA and 1/10 for anti-LKM-1 are significant Hypergammaglobulinemia, largely IgG

Diagnosis Histology: Imaging: US, MRCP (ASC) dense mononuclear and plasma cell infiltration of the portal areas which expands into the liver lobule Destruction of hepatocytes at the periphery of the lobule with erosion of the limiting plate (interface hepatitis) Connective tissue collapse due to hepatocyte death expanding from portal area into lobule (bridging collapse) Hepatic regeneration with 'rosette' formation Cirrhosis Imaging: US, MRCP (ASC)

Treatment Prednisone 2mg/kg/day (max 40mg) Azathioprine 0.5mg/kg/day Monitor Rx response on LFTs and TBC Manage complications e.g. portal hypertension

Portal Hypertension Liver supplied by both the portal vein (75%) and the hepatic artery (25%) Pressure between portal and hepatic venous systems <5mmHg PH is defined as a portal pressure greater than 10 mmHg or a gradient greater than 4 mmHg.

Portal Hypertension Aetiology can be classified as Prehepatic Intrahepatic (Presinusoidal, sinusoidal and postsinusoidal) Posthepatic Peripherally other complications develop: Peripheral and splanchnic vasodilation Increased cardiac output Shunting Salt and water retention by kidneys, etc

Portal Hypertension Clinically most present with ascites, gastrointestinal hemorrhage, and splenomegally Laboratory workup includes LFTs, blood cell and platelet count, and coagulation. Investigations targeted at underlying liver disease Radiology Portal vein doppler studies Triple phase CT scan MR angiography

Portal Hypertension Management Ascites: Diuretics, low salt diet Variceal bleeding: endoscopy and VBL, Prophylaxis with beta blocker Surgical procedures: TIPS, Rex shunt, etc

Patient I.A. 1. Thyroid profile – within normal limits Results: 1. Thyroid profile – within normal limits 2. Alpha Fetoprotein – 2.4 iu/ml 3. Hepatitis A IgM, Hepatitis C antibody, Hepatitis B surface antigen- Negative 4. CMV IgM – Negative 5. Ferritin – 22.49 ng/mL 6. ANA - Negative 7. Anti ds DNA – Negative 8. Caeruloplasmin – 24.5 mg/dL 9. Anti-smooth muscle antibodies – Positive 10. Anti-liver kidney murosomal antibodies – Negative 11. CT Scan abdomen – Liver Cirrhosis with splenomegaly 12. Liver biopsy- not possible, elevated INR

Patient I.A. Started on Prednisone nad Azathioprine with little improvement. Later results were as follows: Urine copper excretion – 109.85ug/24hr After Penicillamine challenge – 446.96ug/24hr I.A. started on penicillamine with significant improvement

Conclusion Liver disease in older children has a different aetiology Many diseases may present without jaundice Diagnosis is possible with a variety of tests, most of which can be done in the majority of facilities in this country.