Liver diseases

20.5 Liver diseases



Wolfram Haller, Winita Hardikar



Introduction


Liver disease is relatively infrequent in childhood. Early recognition is, however, crucial, as the timing of diagnosis has a significant impact on the outcome of many liver disorders. Chronic liver conditions result in a high burden of care for children and their families.


This chapter aims to promote an understanding of the basic concepts of normal liver function, to introduce the concept of biochemical pattern recognition of liver disease, and to enable appropriate differential diagnosis and investigations in the child with suspected liver injury.



Normal liver anatomy and function


In evaluating liver disease, it is useful to think of the liver as being composed of two morphological and functional subunits. Injury to either compartment gives rise to a specific pattern of symptoms and liver test abnormalities. The first subunit is the parenchymal compartment consisting of hepatocytes, the carriers of anabolic and catabolic enzymes, and non-hepatocytic parenchymal cells. The latter include stellate cells, important for production of fibrous tissue under disease conditions, and the Kupffer cells, resident mononuclear leukocytes fulfilling a crucial role in processing antigens that enter the liver through the portal vein. The second subunit is the biliary compartment consisting of the canalicular and biliary system. This system carries bile produced by the hepatocytes into the bowel, but is also actively involved in resorption of various solutes. Bile acids, comprising 12% of bile, are required for the normal absorption of fat and fat-soluble vitamins in the intestinal lumen.


Blood supply to the liver is predominantly via the portal vein (70%), channelling intestinal nutrients towards the liver. The remaining 30% is provided by the hepatic artery, which supplies oxygen-rich blood to the parenchymal and biliary compartments. The bile ducts are sensitive to reduced arterial flow and may become damaged if hepatic arterial flow is interrupted. Blood flows out of the liver via the hepatic veins, which connect to the inferior vena cava.


The liver plays an indispensable role in whole-body energy homeostasis and provides the necessary enzymatic repertoire for numerous catabolic and anabolic pathways. The main functions of the liver are:



• synthesis of a large number of proteins (e.g. clotting factors and albumin)


• production and excretion of bile


• detoxification and metabolism of endogenous toxins and exogenous drugs


• processing of nutrients – the liver is the central regulator of intermediary metabolism


• immune function


• fluid balance


• regulation of growth and other endocrine functions.



Pattern recognition in acute and chronic liver dysfunction


Assessment of liver dysfunction in the child is part of a diagnostic process involving a thorough clinical history, clinical symptoms and signs, and a complete panel of ‘liver function tests’ (see below). The integration of these results will allow further categorization of the disease process. Depending on which morphological and functional compartment is affected, liver disease can be primarily hepatocellular (parenchymal), biliary (cholestatic) or mixed hepatocellular–biliary, and can finally lead to failure of synthetic and detoxification function. Allocation of laboratory tests to a disease pattern results in more targeted investigations (Fig. 20.5.1).


image

Fig. 20.5.1 Diagnoses and investigations according to the predominant pattern of liver dysfunction. ANA, anti-nuclear antibody; AT, antitrypsin; CT, computed tomography; EBV, Epstein–Barr virus; HAV, hepatitis A virus; HBc, hepatitis B core antigen; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; Ig, immunoglobulin; LKM, liver/kidney microsomal antibody; MCS; microscopy, culture, sensitivity; MRCP, magnetic resonance cholangiopancreatography; pANCA, perinuclear anti-neutrophil cytoplasmic antibody; PCR, polymerase chain reaction; Pi, protease inhibitor; SMA, anti-smooth muscle antibody; US, ultrasonography; UTI, urinary tract infection.



Laboratory patterns of liver dysfunction


The actual term ‘liver function tests’ is a misnomer: not all measurements (e.g. alanine aminotransferase (ALT), aspartate aminotransferase (AST)) actually assess the function of the liver, whereas others (e.g. international normalized ratio (INR)) will not be obtained on request of ‘liver function tests’ on a biochemistry form. For practical purposes, the liver function tests can be divided into four categories, as described below.



Markers of hepatocellular dysfunction: ALT, AST


ALT is a cytosolic enzyme; AST can be found in both cytosolic and mitochondrial compartments. Both catalyse a chemical reaction called ‘transamination’ – hence the term transaminases. Hepatocyte damage resulting from infections, drugs, toxins, immunological or ischaemic insults can result in leakage of these enzymes into the circulation. The levels of ALT and AST do not correlate well with the severity of liver damage; for example, low levels of transaminases can be seen in advanced parenchymal necrosis in acute liver failure. ALT is more specific for hepatocellular injury than AST, as the level of AST is also increased in cardiac or skeletal muscle damage as well as in haemolysis. If there is an isolated rise in ALT or AST, consider extrahepatic causes, such as muscle disease or coeliac disease.



Markers of biliary dysfunction/cholestasis: ALP, GGT, conjugated bilirubin, serum bile acids


Alkaline phosphatase (ALP) is an enzyme of uncertain physiological function. Blockage of bile flow leads to de novo production within the bile duct epithelium and to a rise in serum levels, which takes a few days. ALP levels may therefore be normal in acute biliary obstruction. The specificity of ALP is limited, as it is also found in other tissues including bone, intestine and kidney. ALP concentration is therefore often increased in growing children, particularly rapidly growing adolescents. If there is confusion, the origin of the ALP (i.e. liver or bone) can be tested in the laboratory by determining the so-called isoenzymes.


γ-Glutamyltransferase (GGT) is a more sensitive and specific test for biliary disease, and its level increases with biliary obstruction or inflammation. GGT is also induced by certain medications; therefore, if there is an isolated rise in GGT levels, take a full drug history. Bilirubin is the end-product of enzymatic haem breakdown, a component of haemoglobin. This unconjugated bilirubin is lipid-soluble, can cross membranes such as the blood–brain barrier and is therefore toxic, particularly in small infants. Conjugation of the bilirubin to glucuronide in the liver makes it water-soluble and allows excretion (via a transport protein in the cell membrane) into the small bile ducts, called canaliculi. The conjugated bilirubin then drains through the common bile duct into the duodenum. Damage to the transmembranous transport of conjugated bilirubin (e.g. hepatocellular insult) or blockage of the biliary drainage system (e.g. due to gallstones or biliary atresia) impairs bile flow, leading to a clinical phenotype called cholestasis. The water-soluble conjugated bilirubin flushes back into the bloodstream (conjugated hyperbilirubinaemia), is deposited in the skin (jaundice) and filtered in the kidneys (dark urine). The lack of bilirubin in the intestine results in pale (acholic) stools. Determination of conjugated bilirubin is the most important test in any jaundiced patient. A conjugated bilirubin fraction of more than 20% of total bilirubin is called conjugated hyperbilirubinaemia and indicates liver disease and impaired bile flow (cholestasis). Lack of bile flow also leads to retention and blood accumulation of bile acids and other components of bile. It is not known which of these components is the main mediator of the intense pruritus seen in chronic cholestasis.



Markers of synthetic dysfunction: albumin, INR


Albumin is the most abundant protein produced by the liver with a half-life of 3 weeks. Serum concentrations therefore change slowly in response to acute alterations of synthesis (e.g. in acute liver failure), although albumin is a good marker of chronic synthetic failure. The specificity of a low albumin level is, however, limited as a marker of liver dysfunction. Albumin synthesis is also low in situations of longstanding low protein intake (malnutrition), inflammatory conditions (as a negative acute-phase protein), and can also be lost in the urine (renal disease) or through the intestine (protein-losing enteropathy). The liver synthesizes the majority of coagulation proteins, some of them with the help of vitamin K as a co-factor (factor II, VII, IX, X). Liver synthetic function can therefore be assessed through measurement of the INR. Because most clotting factors have a shorter half-life than albumin (factor VII, 6 hours), the INR is useful in assessing short-term changes in synthetic liver function. In general, an abnormal INR can be attributed to synthetic liver dysfunction if it does not improve 6 hours after a dose of vitamin K.



Markers of impaired hepatic detoxification: ammonia, lactate


Ammonia is a product of protein catabolism. The liver plays a crucial role in metabolizing this neurotoxic solute. In situations of acute or chronic liver failure, increased concentrations of ammonia may play an important role in the development of hepatic encephalopathy. Lactate is an important carrier of energy in the fasting state and is either oxidized in the citric acid cycle or used as a substrate for gluconeogenesis in the liver. Consequently, liver dysfunction leads to a slowing of these metabolic pathways and to accumulation of lactate within the bloodstream. Lactate is therefore a useful marker of pronounced acute and chronic liver dysfunction.



Clinical signs of liver dysfunction


A thorough history and clinical examination are essential to guide the diagnostic approach in a child with suspected liver disease. When trying to identify the cause of liver disease, it is useful broadly to categorize children into infants versus older children, acute versus chronic liver disease, and biliary (cholestatic) versus hepatocellular injury. Of course, there will be significant overlap, but the categories are described in detail below and in Table 20.5.1 and Fig. 20.5.1.


Table 20.5.1 Clinical and aetiological categories of liver disease in childhood













Mode of presentation Time of presentation
Infancy Older child
Acute Infectious

• urinary tract infection


• bacterial sepsis


• congenital (TORCH)


Biliary/obstructive



• inspissated bile (sludge)


• cholelithiasis


Metabolic



• galactosaemia


• hereditary fructose intolerance


• Niemann–Pick C disease


• fatty acid oxidation defect


• mitochondrial disease


Ischaemic



• neonatal asphyxia


Immunological



• neonatal haemochromatosis

 Infectious

• viral hepatitis (A, B, E, rarely C)


• non A–E hepatitis


Biliary/obstructive



• cholelithiasis


Metabolic



• Wilson’s disease (acute-on-chronic)


• mitochondrial disease


Drug-induced



• paracetamol


• antibiotics


• antiepileptics (e.g. valproate)


• contraceptives

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Aug 4, 2016 | Posted by in PEDIATRICS | Comments Off on Liver diseases

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