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Liver Failure


Pediatric liver disease is a significant cause of morbidity and mortality worldwide. Advances in diagnosis and treatment, including the successful development of transplantation, have dramatically improved the natural history and outcome for infants and children.

Liver failure is a loss of the synthetic properties of the liver. The antecedent cause may be the progression of chronic liver disease or hepatocellular necrosis in acute liver failure (ALF). This chapter explores the etiology and pathogenesis of liver failure and links with Chapter 78 , which describes the indications for and outcome of liver transplantation (LTx).

Chronic Liver Failure

Pathogenesis

Hepatic Fibrosis to Cirrhosis

Chronic liver disease denotes ongoing liver injury and inflammation for a period of at least 6 months. The histologic description of liver disease is reported as the grade of inflammation (mild to severe) and stage of fibrosis. Fibro-portal tract expansion is described in Stage 1, bridging portal tracts/fibrosis (fibrous tissue traversing to adjacent portal tracts or central vein) in stage 2. The finding of discrete fibrous nodules in stage 3 hepatic fibrosis amounts to cirrhosis. , This progression of fibrosis to cirrhosis, if unmitigated, leads to end-stage liver disease and chronic liver failure.

Significant progress has been made in understanding the mechanisms of hepatic fibrosis. , The hepatic stellate cell (HSC) is a resident peri-sinusoidal cell derived from the embryonic mesoderm and is the primary source of extracellular matrix (ECM) in liver fibrosis. HSC activation in disease follows a process of initiation , which may be triggered by soluble mediators (reactive oxygen species, apoptotic bodies, lipopolysaccharides, and paracrine stimuli), and perpetuation , a cellular phenotypic change of HSC into contractile myofibroblasts that promote mitogen-mediated proliferation, altered matrix degradation, chemotaxis, and proinflammatory signaling. , This cascade of events culminates in a highly fibrogenic environment that ultimately progresses to cirrhosis. During the course of fibrosis, the ECM is constantly remodeled with deposition of new collagens (predominantly type I) and matrix glycoconjugates (proteoglycan, fibronectin, and hyaluronic acid). ,

These pro-fibrotic processes are regulated by a growing number of stimuli and molecular pathways, involving key factors such as connective tissue growth factors, transforming growth factor β1 (TGF-β1), platelet-derived growth factor (PDGF), cytokines, endothelin-1 (ET-1), matrix metalloproteinases (MMPs), and their tissue inhibitors (TIMPs). , The growing understanding of the molecular mechanisms involved in fibrosis has provoked an interest in developing targeted therapy such as cytokine antagonists, MMP inducers, and angiogenesis inhibitors. Vascular adhesion protein-1 (VAP-1), an adhesion molecule produced by the hepatic sinusoidal endothelial cells, is found to be persistently elevated in patients with chronic liver disease and is postulated to be a driver of hepatic fibrosis. Noninvasive biomarkers for staging liver fibrosis—for example, hyaluronic acid levels—have been investigated and sufficiently reflect disease severity. , Liver cirrhosis is the advanced stage of liver fibrosis and is the common endpoint of many different liver diseases. Key morphologic features that characterize cirrhosis include diffuse fibrosis, nodule formation, regeneration, altered lobular architecture, and the establishment of intrahepatic vascular shunts between afferent (portal vein and hepatic artery) and efferent (hepatic vein) liver vasculature.

The pattern of progression to cirrhosis and decompensation is variable. In neonatal extrahepatic biliary atresia (BA), the development of hepatic fibrosis is rapid, with cirrhosis occurring by 8 to 16 weeks of age, whereas in cystic fibrosis (CF)–associated focal biliary cirrhosis, liver function may be normal for many years before the development of cholestasis and clinically evident liver disease. The importance of genetic modifiers on outcome and progression of chronic liver diseases is under investigation. Recently, genetic determinants in the form of single-nucleotide polymorphisms (SNPs) within genes that may contribute to stellate cell activation or hepatic injury have been uncovered. Irrespective of the type of injury, the significant architectural distortion in a cirrhotic liver leads to shunting of portal and arterial blood supply into the hepatic outflow (central veins), thereby compromising exchange between hepatic sinusoids and hepatocytes. The corollary of this is (1) impaired hepatocyte function, (2) increased resistance to portal blood flow, that is, portal hypertension (PH), with its relative complications, and (3) the increased risk for the development of hepatocellular carcinoma (HCC).

Portal Hypertension

PH is defined as a portal venous pressure of greater than 10 mm Hg and occurs when there is increased (1) portal resistance or/and (2) portal blood flow. The hepatic vein to portal gradient (HVPG) provides an estimate of the pressure gradient between the portal vein and the inferior vena cava; a HVPG of greater than 10 mm Hg signifies clinically evident PH with portosystemic collateral development: for example, esophageal, gastric, or rectal varices; or splenomegaly with associated hypersplenism, ascites, and encephalopathy. There is a high risk of a variceal bleed when the HVPG reaches above 12 mm Hg. ,

The underlying etiology of this raised portal pressure falls into three categories: ,

  • 1.

    Prehepatic. This is a common cause of PH in children and is usually due to extrahepatic portal venous obstruction from (usually a historic) thrombus formation. There may have been instrumental umbilical venous access in the neonatal period. Patients need a thrombophilia screen and hematology consultation.

  • 2.

    Intra-hepatic. This can be further subdivided into presinusoidal—for example, congenital hepatic fibrosis or sinusoidal cirrhosis of any etiology—or postsinusoidal—for example, veno-occlusive disease.

  • 3.

    Posthepatic. This is rare and results from hepatic venous outflow obstruction, such as Budd-Chiari syndrome or extrinsic compression of the hepatic vein from a tumor. Functional hepatic outflow obstruction due to right-sided heart failure can also occur.

Three characteristic endoscopic findings may be seen in combination or alone in the child with PH: (1) esophageal varices, which are graded according to their size from 1 to 3 and are predominantly concentrated at the lower esophagus, (2) gastric varices, which are usually an extension of the esophageal varices and are thus located around the fundus, and (3) portal gastropathy, whereby increased gastric mucosal blood flow causes congestion, erythema, and friable mucosa which can bleed. , Red color or cherry red signs signify a high risk of a variceal bleed. ,

Causes of Chronic Liver Failure

Chronic liver failure is the end result of many of the disease processes discussed in previous chapters ( Box 77.1 ). Regardless of the underlying etiology, the replacement of liver tissue by fibrosis, scar tissue, and regenerative nodules, associated with a critical increase in intrahepatic resistance and PH, leads to a turning point between compensated liver disease and liver failure (i.e., disease decompensation). Liver failure marks the loss of the synthetic properties of the liver and the development of complications, which can include malnutrition, fat-soluble vitamin (FSV) deficiency, impaired protein synthesis, coagulopathy, PH and variceal bleeds, encephalopathy (which can be subtle to detect in children), ascites, and the hepatorenal and hepatopulmonary syndromes (HPSs). Furthermore, many children with chronic liver disease have impaired immune function due to diminished hepatic production of immunoglobulins and complement, as well as malnutrition, which together predispose to significant bacterial infections, such as cholangitis, bacterial peritonitis, and sepsis. HCC may also complicate childhood liver disease, particularly in chronic hepatitis B, tyrosinemia type I, and progressive familial intrahepatic cholestasis type 2 (PFIC-2/anti-bile salt export pump [BSEP] deficiency).

BOX 77.1
Chronic Liver Failure
HAV , Hepatitis A virus; HBV , hepatitis B virus; HEV , hepatitis E virus.

  • Cholestatic liver disease

    • Biliary atresia

    • Alagille syndrome

    • Progressive familial intrahepatic cholestasis (types 1, 2, 3, and 4)

    • Idiopathic neonatal hepatitis

      • Choledochal cyst

      • Drug induced

  • Metabolic liver disease

    • α 1 -Antitrypsin deficiency

    • Tyrosinemia type I

    • Wilson disease

    • Cystic fibrosis

    • Glycogen storage type III and IV

  • Chronic hepatitis

    • Autoimmune with or without sclerosing cholangitis

    • Viral (HBV, HCV, and HEV in the immunocompromised)

    • Nonalcoholic steatohepatitis

    • Fibro-polycystic liver disease with or without Caroli syndrome

    • Primary immunodeficiency

  • Vascular causes

    • Budd-Chiari syndrome

    • Veno-occlusive disease

    • Right heart failure

Clinical Presentation

In compensated liver disease , children are usually asymptomatic and there may be no clinical signs. Patients may complain of nonspecific symptoms such as nausea, vomiting, anorexia, lethargy, and abdominal pain. The first indication of liver disease may be an incidental finding of hepatosplenomegaly, splenomegaly alone, and/or raised serum transaminases. Stigmata of chronic liver disease may be evident: jaundice, ascites, digital clubbing, and cutaneous manifestations such as spider angiomata/nevi, palmar erythema, and prominent periumbilical veins. Spider angiomata are mostly found in the upper trunk and can occur in healthy young children or in teenagers during puberty, but more than five or six and/or the appearance of new spider angiomata suggest liver disease. The development of portosystemic collateral vessels due to PH accounts for the dilated and tortuous periumbilical veins. Gynecomastia and asterixis are stigmata that are uncommon in children.

Patients with cholestatic disease may present with pruritus, dark urine, and pale stools in addition to jaundice. The liver is usually enlarged, and xanthomas, malnutrition, and deficiency of FSVs (particularly vitamins D and K) may be prominent features.

In some children, the first presentation of chronic liver disease may be from a variceal bleed with hematemesis, coffee ground vomitus, and/or melena, which can be life threatening. Children can also have recurrent epistaxis due to bleeding from telangiectasia of Little’s area in the nasal mucosa.

Patients with HPS will experience breathlessness on exertion, even with daily activities such as walking to school. It is important to screen for this serious complication, which reportedly affects up to 20% of children with chronic liver disease; polycythemia may be observed before the onset of detectable hypoxia. Extrahepatic features of certain diseases may be apparent. A good example of this is Wilson disease, whereby there may be neurologic involvement manifesting as personality changes or poor performance at school, extrapyramidal signs like dysarthria, tremor, and dystonia, and other archetypal features such as Coombs-negative hemolytic anemia and ophthalmic findings such as sunflower cataracts and Kayser-Fleischer rings, which are best seen on slit-lamp examination of the cornea.

Decompensated liver disease is characterized by clinical and laboratory findings of liver synthetic failure and the occurrence of the complications mentioned above. The liver is enlarged, firm, or nodular in early cirrhosis but becomes shrunken, small, and impalpable in advanced cirrhosis. Splenomegaly from PH will be evident, and stigmata of chronic liver disease are often present.

Malnutrition with reduced lean tissue and fat stores and poor linear growth is an important sign of chronic liver disease in children. The assessment of malnutrition should be performed using a number of parameters, such as triceps or subscapular skinfolds, mid-arm circumference, and arm muscle measurements (mid-arm muscle area). Triceps skinfold and mid-arm circumference are useful indicators of body fat and protein; serial recordings can demonstrate early loss of fat stores before weight and height changes become obvious. Although linear growth is a sensitive parameter, it indicates growth stunting and is a late sign of growth failure.

Spontaneous bruising caused by reduced synthesis of clotting factors and thrombocytopenia due to hypersplenism is a sign of advanced disease. Pancytopenia can result from splenic sequestration, but blood cells are functional despite being lower in number. Splenomegaly can be massive but rarely requires specific intervention; patients and parents should be advised that the child should avoid contact sports and hobbies whereby blunt abdominal trauma from a fall can occur: for example, skiing, trampolining, or horse riding.

There may also be changes in the systemic and pulmonary circulations, with arteriolar vasodilation, increased blood volume, a hyperdynamic circulatory state, and cyanosis due to intrapulmonary shunting. Renal failure is a late but serious event. Laboratory investigations may reveal increased levels of alkaline phosphatase, bilirubin, hepatic transaminases, and ammonia, but in particular, there is abnormal liver synthetic function, reflected by such findings as hypoalbuminemia and prolonged prothrombin time (PT).

Diagnosis of Chronic Liver Disease

Diagnosis of chronic liver disease is based on clinical findings and is guided by the results of investigations including laboratory and genetic studies, radiological imaging, and liver histology. The results of liver biopsy findings will confirm the severity of fibrosis and possibly the cause of the liver disease.

Investigations

Biochemical Liver Function Tests

Biochemical liver function tests ( Table 77.1 ) reflect the severity of hepatic dysfunction but rarely provide diagnostic information about individual diseases. Plasma albumin levels and the PT are the most important tests to perform as they reflect the liver synthetic function. The trend of serial measurements will reflect the patient’s liver status. Low serum albumin indicates chronicity of liver disease, whereas abnormal coagulation indicates significant hepatic dysfunction, either acute or chronic. As FSV deficiency is a complication of chronic liver disease, a high PT may be due to low vitamin K levels. Clotting factors II, VII, IX, and X are vitamin K dependent. Therefore, it is imperative to trial a correction with vitamin K supplementation and reassess. Fasting hypoglycemia in the absence of other causes (e.g., hypopituitarism or hyperinsulinemia) indicates poor hepatic function and is a guide to prognosis in ALF. Diagnostic tests are summarized in Box 77.2 .

TABLE 77.1
Liver Function Tests
Reference Range of Test Abnormality
Conjugated bilirubin <20 mmol/L Elevated: hepatocyte dysfunction or biliary obstruction
Aminotransferases
Aspartate aminotransferase (AST) <50 U/L
Alanine aminotransferase (ALT) <40 U/L		 Elevated: hepatocyte inflammation or damage
Alkaline phosphatase (ALP) <600 U/L
(age dependent)		 Elevated: biliary inflammation or obstruction
γ-Glutamyl transferase (GGT) <30 U/L
(age dependent)		 Elevated: biliary obstruction/enzyme induction, e.g., drug induced
Low in PFIC-1, -2, and -4. High in PFIC-3.
Albumin 35–50 g/L Reduced: chronic liver disease
Prothrombin time (PT) 12–15 s
Partial thromboplastin time (PTT) 33–37 s		 Prolonged:

  • 1.

    Vitamin K deficiency

  • 2.

    Reduced hepatic synthesis

Ammonia <50 mmol/L Elevated: hepatic encephalopathy, abnormal protein catabolism, urea cycle defect, or other inherited metabolic disease
Glucose <4 mmol/L Reduced: acute or chronic liver failure, storage disorders, e.g., glycogen storage disease (GSD), inherited metabolic disease, e.g., inborn errors of metabolism with gluconeogenesis or fatty oxidation defects, and endocrine causes, e.g., hyperinsulinemia, hypothyroidism, hypopituitarism
GSD, Glycogen storage disease; PFIC, progressive familial intrahepatic cholestasis.

BOX 77.2
Investigation of Chronic Liver Disease in Children
ANA, Anti-nuclear antibody ; BMI, body mass index ; ANCA, anti-neutrophil cytoplasmic autoantibody; CF, cystic fibrosis; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HbA1c, glycated hemoglobin; HLA, human leukocyte antigen; LAL, lysosomal acid lipase; LC-1, liver-cytosol 1 antibody ; LKM, liver-kidney microsomal antibody ; LP, liver-pancreas antibody ; PELD, pediatric end-stage liver disease; PHD, pediatric hepatic dependency; PFIC, progressive familial intrahepatic cholestasis; SERPINA1, serine protease inhibitor A1AT; SMA, anti–smooth muscle antibody ; SLA, soluble liver antigen; TORCH, toxoplasma, rubella, cytomegalovirus, herpes simplex; tTG, tissue transglutaminase.

General

  • Bilirubin; conjugated and unconjugated fractions

  • Aminotransferases; alanine transaminase, aspartate transaminase

  • γ-Glutamyl transferase

  • Alkaline phosphatase

  • Albumin

    • Total protein

  • Cholesterol

  • Urea and creatinine

    • Sodium

    • Potassium

    • Bone profile; calcium, phosphate

    • Magnesium

  • Ammonia

  • α-Fetoprotein

    • Amylase/lipase

    • Ferritin

    • Creatine kinase

    • Complete blood count

    • Blood film

    • Coombs test

  • Prothrombin time

    • Partial thromboplastin time

    • Fibrinogen

    • Fat-soluble vitamin levels (A, D, E, and K)

  • PELD or PHD score

  • Chest x-ray: e.g., to screen for butterfly vertebrae

  • Hepatobiliary and renal ultrasound

    • Magnetic resonance imaging with contrast: for anatomic clarification of liver nodules/lesions, for example

    • Magnetic resonance cholangiopancreatography

    • Upper gastrointestinal endoscopy

  • Electrocardiography

  • Electroencephalography (if suspicious of encephalopathy)

  • Liver biopsy

    • Ophthalmology and slit-lamp examination: e.g., to screen for Kayser-Fleischer rings in Wilson disease, for posterior embryotoxon in Alagille syndrome

Specific (for Diagnosis)

  • Viral serology (TORCH screen, hepatitis B, C, EBV, CMV)

  • Autoimmune liver disease

    • Autoimmune antibodies (ANA, SMA, LKM, LC-1, SLA/LP, ANCA)

    • Immunoglobulins (IgG, IgA, IgM)

    • Complement C3, C4

  • Wilson disease

    • Plasma copper or ceruloplasmin level

    • Copper, dry weight of liver biopsy sample

    • Penicillamine challenge

  • Nonalcoholic fatty liver disease

    • Diagnosis of exclusion

    • Steatosis on ultrasound

    • Fibroscan

    • Glucose, HbA1c

    • Lipid profile

    • Blood pressure

    • Weight/Height ± BMI

  • Celiac screen

    • IgA tTG with IgA level

    • consider HLA DR2 and DR8 if positive tTG or highly suspicious of celiac disease

    • Endoscopic duodenal biopsy

General/Metabolic

  • Urinary sugars, amino acids, organic acids, and bile acids

  • Fasting blood tests (glucose, lactate, 3-hydroxybutyrate, free fatty acids, cortisol level)

  • Serum amino acids

  • Serum acylcarnitine profile

  • Serum α 1 -antitrypsin level, followed up with SERPINA1 gene analysis if abnormal

  • Immunoreactive trypsin, sweat test, CF mutation studies

    • Thyroid function tests

    • Serum bile acids

    • Very long chain fatty acids

    • Lysosomal acid lipase enzyme level (measured on dried blood spots, peripheral blood leukocytes, and fibroblasts) to screen for LAL deficiency/Wolman disease

    • Glycogen storage enzymes

    • White cell enzymes (lysosomal storage disease)

  • Liver biopsy histology, immunohistochemistry, electron microscopy

  • Muscle biopsy—respiratory chain enzyme assays

  • CSF chemistry (glucose, lactate, pyruvate amino acids)

Genetic Tests (Diagnosis)

  • ATP8B1 (PFIC-1)

  • ABCB11 (PFIC-2)

  • ABCB4 (PFIC-3)

  • TJP (PFIC-4)

  • JAG1 (Alagille syndrome)

  • NOTCH2 (Alagille syndrome)

  • NPC1, NPC2 (Niemann-Pick disease type C1, Niemann-Pick disease type C2)

  • SERPINA1 (α-1-antitrypsin deficiency)

  • NR1H4 (Farnesoid X receptor, FXR—bile acid metabolism)

  • SLC25A13 (Citrin deficiency, a cause of neonatal intrahepatic cholestasis)

  • VIPAS39 and VPS33B (Arthrogryposis, renal dysfunction, and cholestasis syndrome)

  • LIPA (LAL deficiency)

Vascular

  • Doppler images of hepatic venous blood flow

  • Magnetic resonance angiography

Genetic Tests

Newer, more advanced DNA sequencing techniques, such as whole exome sequencing (WES) and whole genome sequencing (WGS), collectively referred to as next-generation sequencing (NGS), are now feasible. WES enables detailed analysis of the protein-coding region of any given gene to identify genetic variations; this is an efficient method of extensive mutational analysis as the majority of mutations occur on the exons. WGS sequences the entire genome, detailing all the nucleotides that make up a person’s DNA, and is thus more comprehensive than WES.

The downside and limitation of WGS and WES is the resultant discovery of many genetic variants of unknown significance, which can be misleading and be misinterpreted. Targeted NGS gene panels, which are tailored to the select genes of interest, are more useful in screening, for example, for neonatal cholestasis (see Box 77.2 ) and for diagnosing inborn errors of metabolism such as glycogen storage disorders, mitochondrial cytopathies, or nonalcoholic fatty liver disease (NFALD).

NGS therefore has revolutionized the diagnosis of monogenic liver disease, and as these investigations become more sophisticated, we will be able to diagnose liver diseases faster, implement treatment early, and prevent disease progression.

Radiology

Several radiologic techniques provide valuable information in the investigation and diagnosis of pediatric liver disease. Chest x-rays may show skeletal abnormalities; for example, butterfly vertebrae in Alagille syndrome (AGS) or a dilated heart secondary to cirrhotic cardiomyopathy. Plain radiographs are useful in confirming hepatic osteodystrophy: for example, wrist and knee x-rays will demonstrate bone age and/or the development of osteopenia or osteomalacia (rickets) in chronic liver disease.

Ultrasound

Sonographic investigation of the abdomen will reveal the presence of ascites and provides information on the size and echogenicity of the liver and spleen. Doppler assessment of the hepatic vessels provides essential information on vessel patency and speed and direction of blood. Cirrhosis is suggested if there is abnormal homogeneity of the liver architecture and an irregular liver edge. PH is indicated by splenomegaly and splenic or gastric varices. Further vascular findings supportive of PH include decreased antegrade flow volume of the portal vein, lack of respiratory variation of portal venous flow, increased hepatic artery resistive indexes (RIs), and reversal of flow direction in the portal vein (hepatofugal as opposed to the normal hepatopetal flow pattern).

Computed Tomography

Computed tomography (CT) scanning of the liver is usually not required for the diagnosis of chronic liver failure. Intravenous contrast medium causes enhancement of vascular lesions and the walls of abscesses, and it may be helpful in differentiating tumors from other solid masses. CT scans of the brain are helpful for the detection of cerebral edema in ALF.

Endoscopic Ultrasound

Endoscopic ultrasound (EUS) is an imaging modality that visualizes the lower biliary tree. The technique uses mini probes (external diameter 2.6 mm), which are small enough to be passed via the operating channel of conventional pediatric endoscopes. EUS has also proved useful in the diagnosis of submucosal esophageal and gastric varices.

Hepatic Elastography

Transient elastography (TE) is a relatively novel, fast, noninvasive technique that can be performed in the clinic setting and involves the acquisition of pulse-echo ultrasound signals to measure liver stiffness. The normal range of liver stiffness is reported at 4 to 6 kPa, and stiffness in cirrhosis is greater than 12 to 14 kPa. Increasing liver stiffness with increasing hepatic fibrosis has been well documented in adult patients with liver disease of mixed etiology. The few studies that have evaluated the use of TE in children are encouraging. One large French study, comparing different noninvasive methods of assessing liver fibrosis in 116 children with chronic liver disease, found Fibroscan measurements to have a superior correlation with liver biopsy findings compared to aspartate transaminase–to–platelets ratio index (APRI) and the FibroTest. ,

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) is very useful for the identification and demarcation of hepatic tumors and/or regenerative nodules. It provides valuable information on liver and/or brain tissue consistency, storage of heavy metals such as iron in hemochromatosis or copper in Wilson disease, and cerebral edema in ALF.

Magnetic resonance angiography (MRA) has replaced hepatic angiography as the gold standard used for describing vascular anatomy or diagnosing hepatic tumors. The arterial phase provides information regarding the celiac axis, hepatic and splenic artery abnormalities, vascularization and anatomy of hepatic tumors, hepatic hemangiomas, and detection of hepatic artery thrombosis. The venous phase provides information on the patency of the portal, splenic, and superior mesenteric veins and the presence of PH by identification of mesenteric, esophageal, or gastric varices.

Magnetic resonance spectroscopy (MRS) is an increasingly useful method in analyzing cellular processes that are altered by the presence of metabolic abnormalities. MRS may identify a pathologic metabolite or a disruption in the ratio of commonly observed metabolites and has been a particularly useful aid in the diagnosis of inborn errors of metabolism such as urea cycle disorder, where the key feature is the elevation of glutamine in the brain and mitochondrial disorders via the demonstration of lactic acidosis in the brain. MRS has also proven to be an accurate method for the quantification of hepatic fat content. In this setting, MR of hydrogen proton in water and triglyceride moieties can be identified by their unique signal and the cumulative signal amplitude quantified, thereby allowing the fat fraction to be determined.

Endoscopy

Upper gastrointestinal endoscopy (gastroscopy) using a flexible fiberoptic endoscope is the best way to diagnose esophageal and gastric varices secondary to PH. The technique is normally performed under sedation or general anesthetic. In children with hematemesis, gastroscopy not only provides rapid diagnosis but also enables therapeutic interventions with variceal band ligation, endoscopic sclerotherapy with thrombin injection, or treating bleeding gastric or duodenal ulcers by injecting epinephrine or application of a gold probe. Hemospray is a new hemostatic agent designed for the treatment of upper gastrointestinal bleeding. Its efficacy has been demonstrated in treating adults with peptic ulcer and gastrointestinal cancer–related bleeds and it has been used successfully in some centers to treat children with nonvariceal gastrointestinal bleeds.

Neurophysiology

Electroencephalography (EEG) is mostly used in the assessment of hepatic encephalopathy (HE). It identifies abnormal rhythms secondary to encephalopathy due to either acute or chronic liver failure or metabolic or drug toxicity, including posttransplantation immunosuppression. Triphasic waves are most commonly observed in HE and are a distinctive but nonspecific EEG pattern. EEG may also be of value in determining brain death: flat EEG in the absence of sedation is an indication for withdrawal of therapy.

Liver Biopsy

The diagnosis of most liver diseases requires histologic confirmation; thus, liver biopsies are a routine procedure in specialist centers. An aspiration technique using a Menghini needle (or disposable variant) has a complication risk of 1:1000 liver biopsies and may be performed under sedation with local anesthesia. In fibrotic or cirrhotic livers, a Tru-Cut needle, which removes a larger core, may be necessary. Transjugular liver biopsies, in which the liver is biopsied through a special catheter passed from the internal jugular vein into the hepatic veins, is now possible for children as small as 6 kg and is the only safe way to perform a biopsy if coagulation remains abnormal despite support. The complications of this potentially dangerous procedure are much reduced if it is performed by expert hands in specialized units under controlled conditions.

Percutaneous needle liver biopsy interpretation may be difficult because of fragmentation of the specimen or if the specimen is taken from a regenerative nodule, which may look almost normal, although there may be hyperplasia of the hepatocytes or a relative excess of hepatic vein branches. Specific histologic patterns may be diagnostic, such as a plasma cell or lymphocytic portal infiltrate with piecemeal necrosis and interface hepatitis in autoimmune hepatitis (AIH), steatosis and Mallory hyaline and copper deposition in Wilson disease, and intracellular periodic acid-Schiff–positive, diastase-resistant inclusions in α 1 -antitrypsin deficiency.

Management of Chronic Liver Disease

The primary aims of management are the following:

  • To prevent progressive liver damage by treating the cause

  • To anticipate, prevent, and/or control the complications ( Box 77.3 )

    BOX 77.3
    Complications of Cirrhosis in Children

    • Malnutrition and growth failure

      • Fat-soluble vitamin deficiency

      • Metabolic bone disease

    • Portal hypertension and variceal bleeding

    • Hypersplenism

    • Ascites

    • Encephalopathy

    • Coagulopathy

    • Bacterial infections, spontaneous bacterial peritonitis

    • Hepatopulmonary syndrome

    • Hepatorenal syndrome

    • Cirrhotic cardiomyopathy

    • Hepatocellular carcinoma

  • To consider LTx before onset of irreversible disease

Diagnosis and Prevention of Progressive Liver Damage

In most circumstances, there is no specific therapy for the liver disease, and general supportive management is required.

Cholestatic Liver Disease

BA is the most common cause of cholestatic liver failure in children worldwide with a quoted incidence of 1 in 8000 and is the main indication for LTx (see Box 77.1 ). , The disease is broadly divided into four classes: isolated BA, biliary atresia with splenic malformation (BASM) (a syndrome of polysplenia/asplenia, vascular and cardiac anomalies, ± situs inversus), cystic BA, and cytomegalovirus (CMV)-associated BA. Isolated BA accounts for over 60% of these liver failures, for which there is still no clear etiology. In most cases there is obliteration and destruction of what appears to have been a fully formed extrahepatic biliary system in the weeks after birth. Characteristically, a “well thriving baby” presents with obstructive jaundice with acholic stools within the first couple of weeks of life. If left untreated, the pathology will advance to include the intrahepatic ducts. The diagnosis is based on clinical evidence of biliary obstruction, and the liver histology will demonstrate bile duct obstruction with bile plugs, bile duct proliferation, portal fibrosis, cholestasis, and eventually biliary cirrhosis. If a liver biopsy is performed early (within 4 weeks of birth), the histology may be normal. A small, contracted gallbladder may be noted on ultrasound along with ascites and signs of PH if the disease is advanced. Diagnosis is supported by a hepatobiliary scintigraphy (hepatobililary iminodiacetic acid [HIDA]) scan whereby a radiotracer that is injected into a peripheral vein, usually technetium-99m, will normally circulate to the liver and will be excreted into the bile ducts and stored in the gallbladder along with the bile until released into the small intestine—absent tracer detection in the biliary tree and small bowel indicates bile flow obstruction and thus BA. Oral phenobarbitone is given 5 days prior to this investigation to aid in radiotracer excretion and prevent false positives. Surgical exploration by way of an operative cholangiogram in which direct visualization of dye injection into the biliary tree at laparotomy to assess bile duct patency is considered the gold standard diagnostic test. Macroscopic assessment of the shape, size, and color of the gallbladder and liver can also be made; for example, atretic gallbladder and firm green/cholestatic liver.

Surgical removal of the fibrosed biliary tree and formation of a Roux-en-Y anastomosis (Kasai portoenterostomy) can be performed within the same operation if BA is confirmed—this will achieve biliary drainage in 80% of infants if performed within 8 weeks of birth. It is more likely to be successful if carried out early, in experienced pediatric liver units. Establishment of bile flow is the most important prognostic marker and will usually occur within 3 months of a Kasai portoenterostomy, although it can take up to 6 months.

Many units use a postoperative course of steroids to reduce inflammation immediately following the operation, and the benefit remains unproven, although a recent study has demonstrated an increased likelihood of clearing jaundice with steroid use with apparent improved native liver survival. Medical management consists of a 2-week tapering course of steroid (methylprednisolone 20mg/day reducing by 2.5mg daily until the patient is on 5mg/day before switching to Prednisolone 5mg/day). Post-Kasai management focuses on the prevention of ascending bacterial cholangitis, nutritional support/growth failure management, FSV supplementation, and screening for and managing chronic liver failure and its complications. Prevention of cholangitis is with low-dose oral antibiotics (e.g., amoxicillin, 125 mg/day; cephalosporin, 125 mg/day; or trimethoprim, 120 mg/day). If surgery is unsuccessful, or recurrent cholangitis is a problem, chronic liver failure with the development of cirrhosis and PH is inevitable and an indication for LTx.

AGS is an autosomal dominant multisystem condition with variable phenotypic expression. It has an estimated frequency of 1 in 30,000. Systemic involvement includes cholestatic liver disease, growth failure, facial markers (triangular facies, broad prominent forehead, deep-set eyes, and a small pointed chin), ocular symptoms (posterior embryotoxon), cardiac defects (peripheral pulmonary stenosis, tetralogy of Fallot), renal involvement (renal tubular acidosis/glomerulonephritis), and vascular (arteriovenous malformations) and skeletal abnormalities (butterfly vertebrae). There is a lifelong risk of intracranial hemorrhage due to raised intracranial pressure, and therefore regular fundoscopy to screen for papilledema is warranted. Paucity of intrahepatic bile ducts is the chief liver histologic finding. Ninety-five percent of patients with AGS are found to have a mutation in the JAG1 gene, which encodes Notch signaling pathway ligand Jagged-1, with the remainder having a mutation in Notch 2. Patients with Notch 2 defects are more prone to renal disease. Despite an underlying genetic cause, there is a lack of genotype–phenotype correlation in AGS, with mutations being largely sporadic and a range of phenotypes found in affected members of the same family. The outcome of AGS is therefore highly variable. Thirty-three percent of those with AGS and liver involvement require LTx, with neonatal conjugated hyperbilirubinemia a significant risk factor for progressive disease. Good nutritional support, FSV replacement, and treatment of pruritus are key. A recent systematic review of AGS in children found pruritus to be the symptom most children complained of and which had a negative impact on their quality of life (QOL). Indeed, intractable pruritus affecting QOL is an indication for LTx. Maximal antipruritic pharmacotherapy should be tried and in some instances, partial external biliary diversion (in patients without established cirrhosis) is indicated. Results of apical sodium-dependent bile acid transporter inhibitors for the treatment of pruritus in AGS are encouraging and have been shown to be safe in phase 2 trials; multicenter phase 3 trials are ongoing.

Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessively inherited cholestatic diseases caused by mutations in the genes responsible for bile synthesis and transport. Currently, four types of PFIC and their gene mutations (in parentheses) have been characterized: PFIC-1 ( ATP8B1 ), PFIC-2 ( ABCB11 ), PFIC-3/MDR deficiency ( ABCB4 ), and PFIC-4 ( TJP2 ). PFIC-1, -2, and -4 uniformly have normal or low γ-glutamyl transferase (GGT) levels, whereas PFIC-3, as with other cholestatic conditions, has high GGT levels. These are rare disorders with an estimated incidence of 1 in 50,000 to 1 in 100,000. As with AGS, maximal pharmacotherapy and partial external biliary diversion operations can be tried. Most patients with PFIC, however, will require LTx in childhood, and this is typically curative for those with PFIC type 3 (PFIC-3). PFIC-1 is associated with many extrahepatic features such as short stature, deafness, diarrhea, and recurrent pancreatitis. These can worsen following transplantation (especially diarrhea), and graft steatosis may develop and progress to cirrhosis with the need for re-transplantation. Disease recurrence secondary to the development of BSEP antibodies has been recognized in children who were transplanted for PFIC-2. Children with PFIC-2 and PFIC-4 are at higher risk of developing HCC. , Trials using apical sodium-dependent bile acid transporter inhibitors in PFIC are in preliminary stages. There is no specific therapy for the remaining forms of cholestatic neonatal liver disease, but supportive and nutritional therapy is essential and may slow the progression of liver disease. For many children with cholestatic liver disorders, LTx is indicated when cirrhosis and PH develop, when malnutrition and growth failure are unresponsive to nutritional support, or when there is intractable pruritus that is resistant to maximal medical therapy or biliary diversion.

Cystic Fibrosis

As long-term survival improves in children with CF, liver disease is recognized more and is reported in 20% of children. In a large prospective study of 170 CF patients, the median age of cystic fibrosis associated liver disease (CFLD) onset was found to be 12 years. Pancreatic insufficiency, male sex, and a history of meconium ileus are recognized risk factors. Liver disease is the third leading cause of death in CF (following pulmonary disease and transplant complications), accounting for 2.5% of overall mortality. Neonatal cholestasis can be the first hepatic manifestation of CF. The newborn screening test measures the immunoreactive trypsinogen (IRT); the child will then go on to have genetic mutation analysis and a chloride sweat test performed if the IRT is high. Sweat tests can be performed when the child is a couple of weeks old and are guided by the expertise of the respiratory physicians. No specific CF gene mutation is associated with CFLD, but those patients with severe genotypes such as the ΔF508 mutation are at higher risk. Mutations in the SERPINA1 gene are thought to increase the risk of CFLD; a recent study, however, found only 1 out of 30 children with CF to have the SERPINA1 mutation, and there was no clinical correlation with liver dysfunction in this patient. Older children usually present with intermittently raised transaminases associated with a high GGT, hepatomegaly (due to steatosis), and/or PH. Focal biliary cirrhosis with progressive periportal fibrosis is the classic histologic lesion described in CFLD.

Management is supportive with emphasis on optimal nutritional therapy, FSV supplementation, and expedited management of PH. High-dose ursodeoxycholic acid (UDCA) (20 to 30 mg/kg/day) is correlated with an improved biochemical response, but concerns have been raised with the development of toxic bile acids with high doses. Authors of a Cochrane review of UDCA use in CFLD published in 2014 concluded that there was insufficient evidence to justify its routine use in CF. Hepatic decompensation is a late feature of CF liver disease, but severe PH with massive splenomegaly is common, and bleeding esophageal varices can be a serious recurrent problem. These children should be managed on a surveillance endoscopy program. LTx is indicated for children with hepatic decompensation, severe malnutrition, and PH unresponsive to medical management. Assessment of pulmonary function is required, because severe lung disease (loss of more than 50% of lung function) may indicate the necessity for a heart, lung, and liver transplantation.

Autoimmune Hepatitis

The incidence of autoimmune liver disease (AILD) is increasing worldwide and at present affects 1 in 50,000 children. It comprises AIH, autoimmune sclerosing cholangitis (ASC), primary sclerosing cholangitis (PSC), and overlap syndrome.

There is a female preponderance of 3:1 in AIH with onset mostly around the teen years. Clinical presentation can be acute or with chronic liver failure and/or PH. The majority of children present insidiously with chronic liver disease and nonspecific symptoms, although there is usually a history of recurrent jaundice with lethargy, fatigue, anorexia, and weight loss. , There are two distinct types of AIH as defined by the presence of non–organ specific autoantibodies: antinuclear antibody (ANA) and/or smooth muscle antibody (SMA) in type 1 and anti–liver kidney microsomal type 1 (LKM-1) and/or anti–liver cytosol type 1 (anti-LC-1) in type 2. The presence of antisoluble liver antigen / liver pancreas antibody (anti-SLA/LP) pertains to a more severe disease course in both types of AIH. Twenty percent of children will have a personal history of other autoimmune conditions and 40% will have a family history of autoimmune diseases such as celiac disease, inflammatory bowel disease (IBD), and thyroiditis. The human leukocyte antigen HLA-DRB1∗03 and HLA-DRB1∗04 has a strong risk association with AIH type 1 and HLA-DR∗07 with AIH type 2. ,

Liver biopsy is diagnostic and comprises characteristic features with various degrees of interface hepatitis, dense plasma cell–rich lymphocytic infiltrate, hepatocellular rosette formation, and emperipolesis. The majority will have an element of bridging fibrosis, and greater than 50% will have cirrhosis at diagnosis. An acute hepatitis with high transaminases; elevated immunoglobulins, particularly immunoglobulin IgG; reduced levels of complement (C3, C4); and non–organ-specific autoantibodies as described above are supportive of the diagnosis. Therapy includes supportive management and initiating immunosuppression with prednisolone 1 to 2mg/kg/day and azathioprine 0.5 to 2mg/kg/day. Over 80% of children with AIH will respond to this first-line therapy. Relapse or AIH flare is common and will occur in over 40% of children within the first year of treatment. True nonresponders (those who do not have biochemical or histologic resolution of AIH despite good compliance and optimal dosing) will need to be placed on second-line therapy such as mycophenolate mofetil (MMF) or tacrolimus. Third-line therapy described in case reports of adult patients has shown promising results and includes rituximab, mammilian target of rapamicin (mTOR) inhibitors such as sirolimus, and tumor necrosis factor α (TNFα) monoclonal antibody with infliximab. Withdrawal of therapy in patients in remission with no or mild stable liver disease have been successful; treatment withdrawal should, however, be avoided around puberty as relapses could be provoked at this time.

ASC, PSC, and overlap syndrome is less common in childhood and is more likely to occur in teenage male patients with IBD (namely, ulcerative colitis). Patients are usually ANA, SMA, and/or anti–neutrophil cytoplasmic antibody (ANCA) positive. Diagnosis is with confirmatory findings on histology and/or radiological imaging, specifically biliary dilatation, “beading,” and stricturing seen on ultrasound and/or magnetic resonance cholangiopancreatography (MRCP). Endoscopic retrograde cholangiopancreatography (ERCP) is not routinely performed in young children. Periductal concentric fibrosis, bile duct proliferation, and fibrous-obliterative cholangitis are described histologic lesions. Interface hepatitis may be present, especially in those with overlap syndrome. Patients tend to be unresponsive to immunosuppression, and the mainstay of management is encouragement of bile excretion with ursodeoxycholic acid (UDCA), optimizing IBD control, and anticipation and prevention of complications of chronic liver disease.

LTx is indicated in children who do not respond to immunosuppression in AIH and who develop end-stage liver failure or biliary cirrhosis in ASC/PSC. , Failure of medical treatment is more likely when established cirrhosis is present at diagnosis. Disease recurrence can occur in 25% of patients and needs to be highlighted at pretransplant counseling. ,

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