Liver Functions and Processes

Liver Functions

• The liver holds 13% of the body's blood supply at any given moment.
• The liver consists of 2 lobes, 8 segments, and 1000 lobules, connected by ducts that combine to form the common hepatic duct.
• The hepatic duct transports bile to the gallbladder and small intestines.
• The liver performs more than 500 vital functions including metabolic(anabolic and catabolic), excretory, synthetic, detoxification, immunological, hematologic(hemopoietic, coagulation) and storage.
• The liver is responsible for protein synthesis, excretion of metabolic wastes, oxidative phosphorylation, breakdown of glycogen, and fatty acid metabolism.
• Synthesis of cholesterol and bile acids occurs in the liver.
• Enzymes such as NADPH, Cytochrome P-450 and Cytochrome reductase systems are found in the liver.

Normal Liver Function Necessities

• Adequate blood flow requires 20-40% of cardiac output, where 25% of blood enters through the hepatic artery.
• The majority of blood flow comes from the portal venous system.
• Oxygen is required, hepatocyte damage can result from hypoxia/hypotension.
• A low-pressure biliary system is necessary for proper liver function.

Introduction to Liver disease in Children

• Neonatal liver disease has an estimated incidence of 1 in 2,500 live births.
• Early recognition is important in neonates and infants, delays in diagnosis can negatively impact the prognosis.
• An example of the possible negative impact of delayed diagnosis is delays in performing Kasai hepatoportoenterostomy for Biliary atresia.
• Early recognition allows for better nutritional support and potentially slows the decline in liver function.
• Timely recognition of severe liver disease in pediatric patients remains a major problem, unfortunately.
• Pediatric liver injury exhibits a finite number of ways which can make it more difficult to diagnose.
• Different disorders often have virtually identical initial presentations.
• Neonates with liver injury almost always present with jaundice.
• The difference between "physiologic hyperbilirubinemia" and hyperbilirubinemia indicative of severe liver disease often needs to be better understood, since the latter can be difficult to diagnose.

Problems That Can Affect The Liver

• The bile flow out of the liver may be blocked.
• An infection/virus can cause inflammation/swelling.
• Metabolic diseases can cause problems with energy production within the cells.
• Drugs and poisons can cause liver disease.
• Poor blood supply can cause liver disease.
• Congenital disorders/infiltrations can cause liver disease.
• Sometimes the cause is unknown: these are known as idiopathic or cryptogenic liver diseases.

Signs and Symptoms of Liver Disease

• There are many different signs and symptoms which depend on the underlying cause.
• It is rare for all signs and symptoms to occur at once.
• Liver damage can occur slowly or very suddenly over time.
• Symptoms include jaundice (yellowing of the skin and sclera), nausea, vomiting, loss of appetite, urine color change (yellow in newborns, dark in older children), and pale stool.
• Further signs include changes in sleep patterns(older children), vomiting/passing blood in stool, nosebleeds, bruising, tiredness and abdominal swelling.
• Other signs include itching (pruritus), poor weight gain or loss and abdominal pain (right upper quadrant or generalized).

Frequent Causes of Liver Disease By Age

Neonates and Infants

• Cholestatic disorders include biliary atresia and choledochal cyst
• Cholestatic disorders also includes the Paucity of intrahepatic bile ducts (e.g. Alagille syndrome).
• Additional cholestatic disorders include Progressive familial intrahepatic cholestasis syndromes (Byler disease and syndrome), Benign recurrent intrahepatic cholestasis, Caroli disease and syndrome (multifocal duct dilatation).
• One other cholestatic disorder is Inspissated bile syndrome (congenital biliary sludge)
• Idiopathic neonatal hepatitis and mimickers includes cystic fibrosis, Alpha 1-antitrypsin deficiency, Hypopituitarism/hypothyroidism, and Neonatal iron storage disease.
• Toxic/pharmacologic injury examples include acetaminophen, total parenteral nutrition, and hypervitaminosis A.
• Tumors can be a cause where they are intra- and extrahepatic
• Viral hepatitis or other infectious diseases include cytomegalovirus, herpes simplex virus/herpes zoster virus/human herpes virus 6, Epstein-Barr virus.
• Additional infections in the neonate include parvovirus B19, rubella, reovirus type 3, adenovirus, enterovirus, bacterial sepsis/urinary tract infection, syphilis, tuberculosis, and toxoplasmosis.
• Metabolic diseases include disorders of peroxisomal function (Zellweger syndrome).
• Further metabolic diseases include bile acid metabolism, urea cycle (arginase deficiency), and amino acid metabolism (tyrosinemia).
• More metabolic diseases include lipid metabolism (Niemann-Pick type C/Gaucher/Wolman) and carbohydrate metabolism (galactosemia, fructosemia, type IV glycogen storage disease).

Older Children and Adolescents

• Hepatitis (viral hepatitis B and C virus) can occur.
• Hepatitis can also be autoimmune, toxic or pharmacologic (e.g. acetaminophen).
• Liver disease can be associated with chronic inflammatory bowel disease, sclerosing cholangitis (autoimmune disorders).
• Parasitic infections can infect the liver.
• Toxins and pharmacologic remedies can hurt the liver.
• Malignancies can affect the liver.
• Wilson disease can cause liver damage.
• Occlusion of the hepatic veins can cause liver damage.
• Fatty liver of pregnancy can occur.
• Fatty liver from obesity,(nonalcoholic steatohepatitis NASH), can occur.
• Hypoxic injury such as Hypotension/ischemia/cardiac failure can hurt the liver.

Diseases causing Jaundice/Elevated Liver Enzymes

Neonates and Infants

• Infections like Bacterial Sepsis (Escherichia coli) can cause jaundice.
• Infections like viral, Hepatitis viruses, Cytomegalovirus, rubella, Coxsackievirus, Echovirus, Herpesvirus, adenovirus can cause jaundice..
• Metabolic disorders like Inherited Alpha 1-antitrypsin deficiency, galactosemia, hereditary fructose intolerance, cystic fibrosis, Niemann-Pick disease, tyrosinemia can cause jaundice.
• Acquired disorders can cause jaundice, Cholestasis and liver disease associated with total parenteral nutrition, hypothyroidism, and panhypopituitarism.
• Idiopathic disorders such as Neonatal hepatitis, progressive familial intrahepatic cholestasis (e.g. Byler disease), Ivemark syndrome, cerebrohepatorenal (Zellweger) syndrome can cause jaundice.
• Malformation of the bile ducts such as Atresia/paucity where Biliary atresia, intrahepatic bile duct paucity, nonsyndromic and syndromic (Alagille syndrome) can cause jaundice.
• Cystic malformations like Choledochal cysts, cystic dilation of the intrahepatic bile ducts (Caroli disease), congenital hepatic fibrosis, polycystic disease of the liver and kidneys can cause jaundice.

Children and Adolescents

• Acute viral hepatitis like HAV, HBV, and HCV can cause jaundice.
• Inherited disorders like Wilson disease, cystic fibrosis, hepatic porphyrias, Dubin-Johnson syndrome, and Rotor syndrome can cause jaundice.
• Malignancies such as leukemia, lymphoma, and liver tumors can cause jaundice.
• Chemicals like hepatotoxic agents, toxins (insecticides, hydrocarbons, alcohol, organophosphates, aflatoxins, hypervitaminosis A, mushrooms, and acetaminophen) can cause jaundice.
• Several parasitic infections such as schistosomiasis, leptospirosis, and visceral larva migrans can cause jaundice.
• Idiopathic or secondary lesions such as chronic hepatitis, inflammatory bowel disease (ulcerative colitis), rheumatoid arthritis, and obesity can cause jaundice.

Diseases Causing Hepatomegaly

Infants and Children

• Storage disorders(Acute: Reye syndrome (fat) and Chronic: glycogenoses, mucopolysaccharidoses, Gaucher disease, Niemann-Pick disease, gangliosidosis, Wolman disease).
• Nutritional problems can Hepatomegaly(total parenteral alimentation caloric overload, kwashiorkor, diabetes).
• Infiltrative disorders such as leukemia, lymphoma, Langerhans cell histiocytosis, granulomas(sarcoidosis, tuberculosis) causes hepatomegaly.
• Congenital hepatic fibrosis may initially present with hepatomegaly.
• Tumors, primary (hepatoblastoma, hematoma, hemangioendothelioma) and metastatic(neuroblastoma, Wilms, tumours gonadal tumors).

Evaluating a patient with possible liver disease

• Evaluation of suspected liver disease includes an accurate history, physical examination and skilful interpretation of signs and symptoms.
• Further evaluation requires judicious selection of diagnostic tests (laboratory & imaging) and liver biopsy (Histopathology).

History taking

• A history may provide clues about the existence and type of liver disease.
• Onset of liver disease may suggest an inborn error of carbohydrate metabolism e.g. inability to metabolize galactose fructose.
• Family history for a suspected genetic disorder suggests an inherited disorder such as tyrosinemia or Byler syndrome.
• Maternal fever/signs of infection suggests sepsis may be the cause of the jaundice in neonates.
• Persistent jaundice in the first month of life with acholic stools can indicate cholestatic disease.
• A flu-like illness that suddenly develops into jaundice with aminotransferase values in the absence of hepatotoxic exposures means Hepatitis A Virus infection.
• Hep. C virus infection is a possibility in patients who have tattoos, use intravenous drugs, or conditions leading to parenterally administered blood products(hemodialysis, hemophilia, surgery).
• Consider potentially hepatotoxic medications e.g. isoniazid, nitrofurantoin, sulfonamides, and non-steroidal anti-inflammatory agents like acetaminophen and ibuprofen).
• Female teenagers who develop jaundice and have histories of acne, intermittent arthritis, and fatigue may have autoimmune hepatitis.
• Patients with immunodeficiencies who may have an infection with cytomegalovirus, Epstein-Barr virus, or retrovirus may become jaundiced.
• Systemic diseases can cause liver involvement such as obesity or cardiac, endocrine, and intestinal disease.

Physical examination

• A thorough physical examination and skillful interpretation of the signs and symptoms can be a useful evaluation tool.

Laboratory tests

• Liver function tests do not measure specific hepatic functions.
• A rise in serum aminotransferase transaminase level reflects liver cell injury
• Increase in immunoglobulin level reflects an immunologic response to injury.
• An elevation in serum bilirubin level may reflect several disturbances of bilirubin metabolism.
• A single biochemical assay provides limited information.
• Cost-efficient to become familiar with which tests can answer specific questions.
• For suspected liver disease, evaluation addresses if the is liver disease present, what is its nature and severity, what treatment is best and available, response to treatment, and prognosis?
• Biochemical tests that detect suspicion of liver disease can include measuring Serum transaminases, bilirubin, alkaline phosphatase, prothrombin time, international normalized ratio, and albumin levels.
• Marked increases in serum aminotransferase levels show liver cell injury in viral hepatitis, drug or toxin-induced liver disease, shock, hypoxemia, or metabolic disease.
• Alanine aminotransferase or ALT aka serum glutamate pyruvate transaminase, SGPT, is specific to liver tissues.
• Aspartate aminotransferase,AST, aka serum glutamic-oxaloacetic transaminase, SGOT is derived from other organs besides the liver.
• Elevated alkaline phosphatase, 5' nucleotidase 5' NT, a γ-glutamyl transpeptidase(GGT) suggest obstruction or inflammation in the biliary tract.
• AST has more predominant rises in alcohol-induced liver injury, fulminant echovirus infection, and various metabolic diseases.
• In chronic liver disease, or intrahepatic and extrahepatic biliary obstruction, AST and ALT elevations are less marked.
• Nonalcoholic steatohepatitis (NASH), known as nonalcoholic fatty liver disease, is found in obese children has elevated serum transaminase levels.
• Alkaline phosphatase(ALP) activity varies considerably with age.
• Growing children have an elevation of serum Alkaline Phosphatase(ALP) from the isoenzyme originating bone in infants and adolescents.
• An isolated increase in ALP results liver function test results are usually normal and do not indicate hepatic or biliary disease.
• 5' NT (5’ Nucleotidase) and Gamma-Glutamyl Transferase (GGT) more commonly increased in cholestatic conditions, and specific for hepatobiliary disease.
• 5' NT is located in sinusoidal and canalicular membranes AMP converts into adenosine.
• 5' NT is not found in bone.
• 5’ NT is raised in obstructive jaundice, parenchymal liver disease and hepatic metastases.
• GGT enzyme activity is high in early life but declines.
• Cholestasis(obstructive disease) involves serum containing regurgitated bile components.
• Total serum and conjugated levels of bilirubin and bile acids have been recorded.
• Predominant elevation of conjugated bilirubin indicates hepatocellular disease with hepatic excretory dysfunction. An a-fetoprotein resurgence indicates function assessment is improving.
• Hepatic synthetic function is shown in serum albumin and proteins levels, and coagulation indices.
• Albumin(hypoalbuminemia occurs when synthesis of albumin can complicate severe liver disease), can be a prognosis factor.
• Serum globulin concentration( elevated gamma-globulin) can occur.
• Higher titers of smooth muscle antibody, antinuclear antibodies, anti-liver-kidney-microsome antibody and antimitochondrial antibody can be found with patients with autoimmune hepatitis.
• Impairment in Hemostatic function means Coagulation indices such as V deficiencies and deficiencies of vitamin k dependent factors can occur severe liver disease and fulminant hepatic failure.
• Prolonged Prothrombin time indicates Malabsorption of vitamin K which the parenteral administration of vitamin K can fix in 24 hours.
• Persistently low VII levels indicates a poor prognosis for liver disease.
• If vitamin k is not responsive hepatic disease can occur.
• Clinical signs occur in the severity of the liver disease such as occurrence of encephalopathy variceal hemorrhage worsening jaundice apparent shrinkage massive necrosis.
• Onset of ascites can occur with the severity of liver disease.
• Biochemical alterations can occur such as hypoglycemia and hyperammonemia or electrolyte imbalance.
• The severity of liver disease comes with continues hyperbilirubinemia with marked hypoalbuminemia or prolonged unresponsive to vitamin K after being administered paratenally.

Liver Biopsy

• Liver biopsy alongside clinical data can help find a definite cause to these diseases.
• Diagnosis can be determined precisely with:

1. neonatal cholestasis,Chronic Active Hepatitis Suspected Reye syndrome Intrahepatic Cholestasis Undefined hypertension

• For enzyme analysis to detect errors of metabolism.
• To analyze amounts of copper,iron, and other certain metabolites.
• Biopsies monitor treatment responses with potentially toxic agents(aspirin,minocycline, antimicrobials).
• In children,needle biopsy is easily taken.
• Percutaneous liver biopsy easily done in children and can safely be taken within 1 week from age.
• Sedation or local anesthesia require.
• Contraindications are prolonged PT&INR, Throbocytopenia, suspiciion of infectious lesson and severe ascites.
• other methods that can be done are Open laparotomy and the Transjugular approach.
• potential issues small risk are hemorrhage, hematoma Creation of an arteriovenous fistula Pneumothorax Bile peritonitis.

Hepatic Imaging Procedures

• To assess these procedures it can help find the size and shape and anatomy of extra and intrahepatic biliary trees.
• Although it needs a histologic test, it can answer what the result can be of hepatomegaly being caused accumulation,cysts or tumors.
• These processes then are sent further to get surgery assistance (percutaneous,obstruction).
• Normal liver assessment is done through examining X rays and physical size with less fat deposit.
• Calcifications (parasitic and neoplastic presence vascular wall tumor) or in the trees of gallbladder.
• gas or fluid Collection (abscess in biliary) within liver.
• Ultrasonography is where size formation blood flow is all determined.
• Increased brightness = fatty tissues and more dense smaller lesions.
• Detect gallstones or stones.
• Size dilatation can be told too.
• Infants show biliary or absense from a common area, they cannot see a duct, there is a cord sign a shape in portal.
• US detects hypertension, amount off flow to the system and assess of ascites.
• Helpful at assessing how transplanted well a liver moves fluids.CTs are suitable for under 2 infants or not of abdominal fat needs to take sedation.
• MRI is useful to see tract lesions well, detect any focal such as liver cancer, cysts, abscess.
• MRI also shows mass that contrast with normal liver tissues.CTs help identify the anatomy/ vascularities of the tumours while revealing liver subtle patterns with it density and fatty deposits. Iron increases while glycogen storage is not.
• CT scans show obstructive from less common ones.
• CTs and US are both used for guiding with needling ( lesions, aspiration) for exam.
• radionuclide test uptake of radiopharma-agents.
• Colloidal Sulfur used kupffer that undergoes phagocytosis.
• Tc: agents that uptake from liver then turns to bile or bilirubin.
• Sulphur collides tumors/cysts to around 2-3 cm. it then detects cirrhosis and with patch uptake from liver then transfer the marrow.
• Gallum 67 finds any neoplasms, inflammatory issues.
• Injected isotope is usually found within 1-2 within the bowel , the extra hepatic excretion will delay it.
• Biliary Atresa: Clearance/Uptake is usually good but is absent from intestine.
• Poor uptake but the excretion of bile is poor(neonatal hepatitis).
• Cholangiography identifies and see bile then used some for obstruction ( location to extent).
• Childern use transhepatic cholangis where children can be the process has a fine. It shows systems.
• Endoscope: Used on childern exam bile with an alternative.
• Vater used a Fiber optic than enters with contrast then outlines systems.
• Xray: angio then sees artery to visualize port and liver walls.
• Angiography is required for surgery. It views flow to hypertension( high or low).
• Assesses of if the system flows correctly, what areas are collaterals and can see if a calibrated vessel for shunt. This can all also provided through MRI