Abstract
The word “cirrhosis” comes from the Greek kirrhos, meaning yellowish, tawny, and describes the gross pathology of the diseased liver. Since the late 1980s, however, clinicians have used the definition provided by the World Health Organization, which defines cirrhosis as a diffuse liver process where fibrosis has resulted in a conversion of the liver architecture into structurally abnormal nodules [1]. This distortion of liver architecture leads to compression of hepatic vascular and biliary structures, creating a further imbalance in the delivery of nutrients, oxygen, and metabolites. Even after the original insult has been controlled or stopped, the cirrhotic state persists. Although the causes of chronic liver disease encompass a wide spectrum of pathophysiological processes, cirrhosis is a common outcome [2].
Introduction
The word “cirrhosis” comes from the Greek kirrhos, meaning yellowish, tawny, and describes the gross pathology of the diseased liver. Since the late 1980s, however, clinicians have used the definition provided by the World Health Organization, which defines cirrhosis as a diffuse liver process where fibrosis has resulted in a conversion of the liver architecture into structurally abnormal nodules [1]. This distortion of liver architecture leads to compression of hepatic vascular and biliary structures, creating a further imbalance in the delivery of nutrients, oxygen, and metabolites. Even after the original insult has been controlled or stopped, the cirrhotic state persists. Although the causes of chronic liver disease encompass a wide spectrum of pathophysiological processes, cirrhosis is a common outcome [2].
Classifications
Schemes for categorizing fibrosis and cirrhosis have been developed based upon gross morphology, microscopic histology (Figures 5.1–5.3), etiology, and clinical presentation. Categorization based upon gross morphology and histology has limited utility because it does not distinguish between the original pathogenic mechanisms of disease. The more commonly used pathologic staging systems (developed for the histopathologic description of the viral hepatitides), METAVIR and Ishak, stage fibrosis by varying degrees of presence of fibrosis, ranging from portal expansion to cirrhosis.
Figure 5.1 Autoimmune hepatitis showing expanded and fibrotic portal tract at bottom with piecemeal necrosis at the limiting plate. (Trichrome stain, magnification ×100.)
Figure 5.2 Biliary cirrhosis in a patient with biliary atresia, showing bile duct proliferation and bile plugging in the bile ducts. (Hematoxylin & eosin stain, magnification ×40.)
Figure 5.3 Biliary cirrhosis in a patient with biliary atresia, showing proliferating bile ducts with bile plugging plus cholestasis in hepatocytes. (Hematoxylin & eosin, magnification ×100.)
Within cirrhosis, many liver diseases have specific histologic patterns (e.g., biliary cirrhosis, hepatocellular cirrhosis, and cardiac cirrhosis) early in the cirrhosis progression; however, as cirrhosis advances, the patterns merge, rendering broad pathological classifications unhelpful. Table 5.1 has a list of disorders that progress to cirrhosis to provide a framework for the diagnostic investigation of cirrhosis, a basis for prognosis determination, and a foundation for genetic counseling.
Table 5.1 Diseases potentially resulting in cirrhosis
| Type | Disorders |
|---|---|
| Metabolic disorders |
|
| Infectious diseases |
|
| Inflammatory diseases |
|
| Biliary malformations |
|
| Vascular lesions |
|
| Toxic disorders |
|
| Nutritional disorders |
|
| Idiopathic diseases |
|
Cirrhosis is now increasingly defined by clinical outcomes rather than pathologic staging systems. When synthetic function of the liver is maintained, the term compensated cirrhosis is used. Within the compensated group, there is a distinctly different prognosis based on the absence or presence of varices. Over time, compensated patients can progress to decompensated cirrhosis, which is defined as the loss of normal synthetic ability of the liver and the development of jaundice or the clinical complications of portal hypertension such as ascites, variceal hemorrhage, and hepatic encephalopathy (HE). The more severe stage of decompensated cirrhosis includes those patients who have developed life-threatening complications of their disease, such as recurrent variceal hemorrhage, refractory ascites, hyponatremia, and/or renal failure.
Pathophysiology
Cirrhosis represents a fluid, dynamic state, wherein the forces of cell injury (necrosis), cellular activation response to injury (fibrosis), and regeneration (nodule formation) compete. It is the derangement of the balance of these three processes that leads to cirrhosis.
Extracellular Matrix, Fibrogenesis, and Regeneration
Extracellular matrix (ECM) proteins have both mechanical and functional roles, contributing to strength of the membrane, modifying vascular flow, and controlling the movement of cells while also serving as ligands and receptors in the cellular signaling pathways. Hepatic fibrosis is a wound healing response characterized by the accumulation of ECM following liver injury. This injury may occur as a result of almost any insult, including viral invasion, immunological dysregulation, ischemia, and toxin exposure. Whereas in the normal liver there is a tightly regulated balance between ECM protein synthesis and breakdown, sustained hepatocellular injury leads to chronic inflammation, excessive ECM protein synthesis, and consequently the development of scar tissue in the liver parenchyma.
The most important and well characterized structural ECM proteins in the liver are collagen, proteoglycans, laminin, fibronectin, and matricellular proteins [3]. In a normal liver, the ECM makes up less than 3% of the area on a tissue slide section and 0.5% of the weight of the liver, primarily in the sub-endothelial space of Disse, primary vascular structures (portal tracts and central veins), and the liver capsule. Following liver injury, the normal matrix of the space of Disse is converted from a collagen IV/VI composition to a matrix composed of collagens I and III and fibronectin. This alteration in compositional structure results in capillarization of the sinusoids and creates an obstruction of flow of plasma between the sinusoidal lumen and hepatocytes, greatly affecting function. These altered sinusoids form conduits from portal to central veins, which shunt blood from the terminal portal veins and hepatic arteries to the central hepatic veins with little direct contact with hepatocytes. As the process advances, connective tissue bands form, which run between portal triads or between portal triads and central veins. These septa may impede blood flow to entire hepatic lobules, resulting in further ischemic damage and cell dropout. The reduction in the amount of viable, well-vascularized hepatic tissue leads to compensatory hepatocellular growth and nodule formation. These hepatic nodules increasingly impede blood flow to the lobules by directly compressing hepatic arterial and venous blood flow. This cycle becomes self-sustaining and can persist independently of the initial insult.
In addition to producing structural molecules, ECM also regulates cellular activity through the production of growth factors and matrix metalloproteinases. Several ECM components bind integral signaling cytokines such as transforming growth factor (TGF)-β, tumor necrosis factor-α, platelet-derived growth factor, hepatocyte growth factor, and interleukin-2. These cytokines activate intracellular signaling pathways that regulate and propagate fibrosis. The principal factor implicated in liver fibrosis is TGFβ, which is produced by monocytes and macrophages.
In a fibrotic liver, ECM proteins can increase up to eight-fold over those in normal liver [4]. If stimulated by inflammatory cells or by various cytokines, hepatocytes and their supportive cells secrete an altered ECM. In order to understand fibrosis, and ultimately to identify new therapies to reverse the disease process, it is important to understand the changes in the proteins and the cells that synthesize them.
The most important cell in the pathogenesis of fibrosis is the myofibroblast, which works to synthesize and deposit ECM. This is a contractile secretory cell that produces α-smooth muscle actin. Prior research has concentrated upon the hepatic stellate cell (HSC), which, after transformation to a myofibroblast, plays an important role in liver fibrosis. Exciting advances since the late 1990s have led to a greater appreciation of the spectrum of cells that can become precursors to myofibroblasts in the damaged liver. It is unclear whether resident or extrahepatic stem cells become or differentiate into the non-parenchymal cells. Endothelial cells (through epithelial to mesenchymal transition), portal fibroblasts, Kupffer cells, and bone marrow-derived myofibroblasts have all been implicated as precursors. Endoplasmic reticulum stress has become increasingly implicated to play a role in the activation on HSCs.
Three conditions are necessary for cells to differentiate into myofibroblasts: (1) high levels of TGFβ, (2) fibronectin splice variant extra domain A, and (3) increased local mechanical tension. These factors act on potential precursors of myofibroblasts to cause them to differentiate. In normal liver, platelet-derived serotonin promotes liver regeneration through the interaction with the 5-HT2A subclass of receptor for serotonin, which is expressed on hepatocytes. In contrast, expression of the 5-HT2B receptor is relatively low in healthy liver but is highly expressed in the activated hepatic stellate cells associated with fibrotic liver. Consequently, these hepatic stellate cells suppress hepatocyte proliferation through their stimulation by serotonin, an act that increases production of TGFβ1, a powerful suppressor of hepatocyte proliferation. Therefore, the regenerative properties of serotonin acting through 5-HT2A receptors on hepatocytes are opposed by the antiregenerative effects of 5-HT2B receptors on hepatic stellate cells [5].
In vitro studies of the liver have shown that mechanical forces at the cellular level can impact cell function, motility, adhesion, contractility, and, most importantly, differentiation state [4]. Mechanical stiffness leads to activation of hepatic stellate cells and expression of α-smooth muscle actin, as well as myofibroblastic differentiation of portal fibroblasts, thus propagating a vicious cycle of increased deposition of stiff matrix leading to increased differentiation, and so on. Mature scars rich in ECM cross-links and elastin are self-propagating and are more difficult to remodel. The clinical correlation is seen in animal models of fibrosis and in patients with chronic hepatitis C infection, where MR elastography studies have shown that hepatitis C-infected livers with no detectable fibrosis can be stiffer than the liver in uninfected patients, and that perhaps liver stiffness precedes fibrosis.
As understanding of the mechanisms underlying hepatic fibrosis increases, effective antifibrotic therapy will be the ultimate goal. Ongoing studies of antifibrotic therapy fall into four categories: (1) controlling or curing the primary disease, (2) targeting receptor-ligand interactions, (3) inhibiting fibrogenesis, and (4) promoting resolution of fibrosis [6]. Treatment trials, the majority of which are employed in the treatment of patients with non-alcoholic steatohepatitis (NASH), have been grouped under these categories. Obeticholic acid, a FXR agonist, and elafibranor, a PPAR alpha and delta agonist, target receptor-ligand interactions. Losartan, a renin-angiotensin-aldosterone-system interfering agent is currently being trialed for the treatment of pediatric non-alcoholic fatty liver disease (NAFLD) [clinicaltrials.gov, NCT03467217].
Fibrosis in human chronic liver disease generally has such a slow evolution that testing in clinical trials is difficult. Additionally, liver biopsy, the gold standard for assessment of liver fibrosis, is not ideal as it is not a rapid, safe, and reproducible way to monitor progression of fibrosis and subsequently the effectiveness of antifibrotic therapy in the liver. The search is ongoing for an ideal serum and/or imaging marker of liver fibrosis. Current non-invasive markers include stiffness assessment by transient elastography, magnetic resonance elastography, or acoustic force radiation impulse imaging. Transient elastography has been correlated with fibrosis severity in adults with an area under the receiver-operator-characteristics (AUROC) curve that is acceptable [7]. Magnetic resonance elastography has similar or superior accuracy with prohibitive cost and time consumption.
The continual regeneration of the liver against the background of altered ECM composition and chronic inflammation predisposes to the development of hepatocellular carcinoma. As management of portal hypertension and other complications of cirrhosis have improved, hepatocellular carcinoma has become a more common clinical event in the adult population as well as the pediatric group [2].
Studies of liver regeneration have largely utilized the two-thirds partial hepatectomy model in rodents to examine the molecular and cellular mechanisms of liver regeneration [8]. Interestingly, in the resection model, regeneration is compensatory hyperplasia controlled by the metabolic needs of the organism. A great deal of work has examined these mechanisms. Because of the extent of cell proliferation and upregulation needed to restore liver mass following resection, and the importance of the liver for survival, hundreds of pathways have been implicated in regeneration; they are highly conserved and redundant.
Clinical Features of Cirrhosis and Portal Hypertension
The clinical presentation of cirrhosis depends on the causative underlying liver disease as well as on the pace of progression of hepatocellular dysfunction and fibrosis. Many children and adolescents present with findings discovered incidentally during routine physical examinations, or as a result of an investigation of an unrelated condition. In others, the discovery of chronic liver disease may be sudden and dramatic, such as with the onset of hematemesis, encephalopathy, ascites, or infection. Compensated cirrhosis, with its preservation of hepatic function despite the cirrhosis, is in contrast to decompensated cirrhosis, where patients suffer from progressive complications of liver disease (fatigue, ascites, variceal bleeding, HE) with associated hepatic dysfunction. Measurement of the hepatic venous pressure gradient is increasingly used to stratify risk of complications of portal hypertension, with a value of >10–12 mmHg representing a critical threshold beyond which features of portal hypertension are generally found [2]. The clinical manifestations of cirrhosis affect children and adults similarly, with the exception of growth failure uniquely affecting children. It is unusual to find all, or even a majority, of these signs in any particular patient, however, and rarely cirrhotic patients can lack any obvious physical or laboratory evidence of their condition. Signs of systemic illness such as failure to thrive, anorexia, easy fatigability, muscle weakness, and nausea and vomiting may be present. Examination of the abdomen may reveal a firm nodular liver edge and the spleen may be enlarged in the setting of portal hypertension.
Ascites is often associated with hypoalbuminemia, steatorrhea secondary to cholestasis, and reduced bile acid availability for fat absorption in the intestine. A history of epistaxis, hematemesis, and hematochezia may be related to coagulopathy of liver disease or to portal hypertension with esophageal and rectal varices. Pallor may be present without bleeding because of the anemia of chronic liver disease. Cyanosis and digital clubbing are often present and are related to chronic hypoxemia secondary to pulmonary–systemic collateral circulation and ventilation–perfusion mismatching (hepatopulmonary syndrome (HPS)). Skin and extremity changes include jaundice, although it is not always discernible by the patient or the patient’s family. Other skin manifestations of chronic liver disease include spider angiomata and palmar erythema. Spider angiomata are easily recognizable as small, raised, dark lesions with radially distributed convoluted vascular branches, and their pathogenesis is related to elevated levels of estrogen secondary to decreased hepatic clearance from systemic circulation. Although it is not unusual to have several spider angiomata, the presence of more than five in the body region drained by the superior vena cava is abnormal and is suggestive of chronic liver disease. Palmar erythema is similarly related to the vasoactive effects of elevated systemic hormones [9]. White nails (terry nails) are often seen in cirrhotic patients, where the nail beds are white with a loss of the lunula and a dark band at the tip. The exact pathogenesis is not known, but biopsies of the nail bed show increased connective tissue and decreased vascularity.
The encephalopathy of liver disease may be prominent, or it may present in subtle forms such as deterioration of school performance, reversal of the sleep–wake cycle, depression, or emotional outbursts. It can be difficult to discern in a child, particularly the very young, and often neurocognitive evaluation is required. A neurologic examination can reveal asterixis (rhythmic hand flapping on wrist extension), a prolonged relaxation phase of deep tendon reflexes, and a positive Babinski sign. Table 5.2 shows physical findings associated with chronic liver disease and cirrhosis.
Table 5.2 Physical findings associated with cirrhosis and portal hypertension
| Body region | Findings |
|---|---|
| General | Poor growth, malnutrition, fever, muscle wasting, fatigue, decreased exercise tolerance, cyanosis |
| Skin and extremities | Jaundice, flushing or pallor, palmar erythema, spider angiomata, digital clubbing, terry nails |
| Abdomen | Distension, caput medusa, ascites, shrunken liver, large spleen, rectal varices |
| Central nervous system | Asterixis, positive Babinski reflex, prolonged relaxation phase of deep tendon refluxes, mental status changes |
| Miscellaneous | Gynecomastia, testicular atrophy, feminization, delayed puberty |
Extrahepatic Complications of Cirrhosis
Patients with cirrhosis may be predisposed to developing pigmented gallstones, which are thought to be related to a decreased bile acid pool, bile stasis, and estrogen-like feminization. The preponderance of pigment stones, however, suggests that hemolysis (secondary to hypersplenism) and abnormal bilirubin metabolism play a primary role in stone formation.
Pulmonary Manifestations
The development of arteriovenous shunts in the lungs has the primary clinical features of respiratory complaints associated with chronic liver disease, HPS. Dyspnea on exertion is the most common complaint. Platypnea (shortness of breath worsened by sitting up) and orthodeoxia (hypoxemia worsened when in the upright position) are the classic findings and result from gravitational increase in the blood flow through the dilated shunts in the bases of the lungs. Other factors that should increase suspicion for HPS are the presence of digital clubbing, development of cough, and decreased oxygen saturation.
Increased lung vascular endothelial endothelin B receptor expression and increased circulating levels of endothelin-1 are thought be central to the development of the intrapulmonary vasodilatation observed in HPS. The onset of HPS may be triggered by endothelin-1 activation of the endothelin B receptor leading to increased nitric oxide production by the endothelial nitric oxide synthase in the pulmonary endothelium. Pulmonary vascular remodeling through angiogenesis is also likely to play a role [10].
Orthotopic liver transplantation is the current preferred treatment for HPS, improving five-year survival from 23% to 76% [11]. Resolution of HPS following transplant can take up to two years. Transjugular intrahepatic portosystemic shunting (TIPS) has been implemented in a limited capacity in children without sufficient results to recommend its use as primary therapy in children with HPS.
In addition to HPS, there is true pulmonary artery hypertension caused by the increased resistance to blood flow that occurs in the setting of chronic liver disease. Diagnosis of portopulmonary hypertension is defined by elevated mean pulmonary artery pressure (at rest >25 mmHg), increased pulmonary vascular resistance, and normal pulmonary artery occlusion pressure in the setting of liver disease and portal hypertension. It is diagnosed by right heart catheterization; in adult liver transplantation candidates, it has been reported to be as high as 8%. Its pathogenesis is incompletely understood, but it is likely related to an imbalance of vascular mediators that favor vasoconstriction, excessive pulmonary blood flow leading to endothelial damage, vascular remodeling, and microvascular thrombosis within the lungs. On autopsy, the vascular changes have been described as medial hypertrophy and endothelial/smooth muscle cell proliferation in the small pulmonary arteries, and are not related to severity of liver disease or degree of portal hypertension [12].
There is a paucity of prospective randomized placebo-controlled trials in portopulmonary hypertension to establish clinical guidelines in children. Conventional management has included diuretics and fluid limitation to avoid fluid overload. Beta-blockers, often used for control of bleeding esophageal varices, are contraindicated as they often worsen exercise capacity and pulmonary hemodynamics. Liver transplant is contraindicated because of the high risk of cardiopulmonary mortality related to perioperative right ventricular dysfunction [13]. However, patients who show clinical improvement of mean pulmonary artery pressure with medical treatment such as prostaglandin analogues (epoprostenol), phosphodiesterase-5 inhibitors (sildenafil), or endothelin receptor antagonists (bosentan, ambrisentan) may benefit from orthotopic liver transplantation with improvement or resolution of portopulmonary hypertension [14, 15].
Hematologic Manifestations
Hematologic changes associated with cirrhosis include anemia and coagulopathy. The anemia of cirrhosis may be multifactorial in cause, including blood loss via the gastrointestinal tract, hemolysis secondary to hypersplenism, iron and folic acid deficiency secondary to malabsorption, malnutrition associated with malabsorption and anorexia, and dilution of red blood cell volume as a result of sodium and water retention. The coagulopathy of cirrhosis also is multifactorial, with a decrease in the synthesis of liver-derived clotting proteins, including prothrombin and factors VII and IX, and increased consumption of clotting factors through increased fibrinolysis and disseminated intravascular coagulation. Malnutrition, vitamin K deficiency, and thrombocytopenia as a result of hypersplenism may exacerbate the problem.
Decreased blood flow through the portal vein predisposes patients toward portal vein thrombosis, which worsens clinical condition associated with pre-existing portal hypertension.
Cardiovascular Manifestations
Cardiovascular manifestations of cirrhosis include a high cardiac output state related to changes in systemic vascular resistance, with peripheral vasodilation, pulmonary vascular resistance, and hepatic blood flow (portal hypertension). The sustained increase in cardiac output results in the flushed appearance of patients with cirrhosis.
Endocrine Manifestations
Endocrine manifestations of cirrhosis result from failure of the liver to conjugate or metabolize hormones and include diabetes mellitus, which may present as subtle hyperinsulinemia without overt signs; hypothyroidism; syndrome of inappropriate secretion of antidiuretic hormone, presenting as hyponatremia; and feminization, including gynecomastia (benign proliferation of the glandular tissue of the male breast) and decreased axillary hair. Gynecomastia results from both the increased production of androstenedione and the increased circulating levels of estradiol. Delayed puberty is common in children with chronic liver disease. Cirrhotic patients also demonstrate relative adrenal insufficiency, where there is an inappropriate plasma cortisol response to adrenocorticotropic hormone [16].
Neurologic Manifestations
Occurrence of HE in chronic liver disease is grouped into stages, as shown in Table 5.3. Changes in consciousness include hypersomnia, reversal of sleep pattern, apathy, slowed speech, decreased spontaneous movement, and eventually coma. Personality changes commonly seen in chronic liver disease include irritability and inability to cooperate. These personality changes can be normal reactions to chronic disease and hospitalization in children, and their true cause may not be understood until frank encephalopathy is present. Intellectual deterioration with slight or gross confusion may be present. Focal defects in visual spatial skills also may appear, even if confusion is not present. The neuropsychological testing that is often used in adults, such as tests of constructional apraxia or the Reitan trail-making test, may be difficult to administer if the child is at too early a developmental stage.
Table 5.3 Stages of encephalopathy
| Stage I | Stage II | Stage III | Stage IV | |
|---|---|---|---|---|
| Mental status | Alert, oriented, irritable; sleep rhythm reversal | Lethargic, confused, combative | Stupor, marked confusion | Comatose; may respond to painful stimuli |
| Motor | Obeys commands; tremor, poor handwriting | Purposeful movement, grimacing, tremor | Local response to pain, intention tremor | Abnormal reflexes, no motor activity |
| Asterixis | Uncommon | Usually present | Present, if cooperative | Unable to elicit |
| Muscle tone | Normal | Increased | Increased | Increased or flaccid |
| Reflexes | Normal | Hyper-reflexic | Hyper-reflexic | Hyper-reflexic/absent |
| Respiratory effort | Normal/hyperventilation | Hyperventilation | Hyperventilation | Irregular |
| Eyes | Spontaneous opening | Open with verbal stimuli | Open with verbal stimuli | Sluggish or fixed; may open eyes with noxious stimuli |
| Electroencephalography | No gross abnormality | Grossly abnormal with slower rhythms | Theta activity and triphasic waves | Delta waves present |
The most characteristic sign of CNS dysfunction is asterixis, a flapping tremor that is demonstrated if the patient’s arms are outstretched and wrists are hyperflexed for 30 seconds. The tremor is absent at rest and present during voluntary movement. Asterixis also is seen in uremia, congestive heart failure, and respiratory failure. Deep tendon reflexes may be exaggerated in early encephalopathy, but in late stages the muscles become flaccid and the reflexes disappear.
Minimal hepatic encephalopathy (MHE), in which patients lack obvious signs and symptoms of encephalopathy but may have subtle symptoms and impairment on neuropsychiatric evaluation, is an entity that has been examined in depth in the adult population. Its incidence in children is unknown. There is increasing concern that early diagnosis and treatment may be important for preservation of brain function, particularly in children, who may be more vulnerable because of their potential brain growth and development. In contrast with patients with onset of liver disease in adulthood, deficits in global intellectual measures in children persist even after liver transplantation [17]. One uncontrolled small study demonstrated the utility of MR spectrography in the detection of MHE in children.
Immunologic Manifestations
Cirrhosis is an immunocompromised state that increases susceptibility to infections, which account for a significant portion of mortality. The most common infections in cirrhotic patients are spontaneous bacterial peritonitis (SBP), urinary tract infections, and pneumonia [18]. Cirrhosis-associated immune dysfunction syndrome is a state of systemic immune dysfunction that results in an attenuated response to clearing cytokines, bacteria, and endotoxins from the circulation because of liver insufficiency. In addition to these factors, phagocytic activity and neutrophil mobility are impaired in cirrhosis through the decreased responsiveness to cytokine signaling. Innate immunity is additionally hampered by a decreased bactericidal and opsonization capacity. The liver is host to key reticuloendothelial cells that play an important role in clearing bacteria from the bloodstream. Loss of normal parenchyma and portosystemic shunting, where blood is directed away from the liver, contribute to overall decreased blood and toxins reaching the liver.
Renal Manifestations
Renal and fluid complications often seen in cirrhosis result from decreased portal flow with compensatory maladaptive splanchnic vascular vasodilatation and decreased effective arterial blood volume, which then leads to activation of the renin–angiotensin system, with increased sodium and water retention. In the setting of hypoalbuminemia and portal hypertension, ascites formation further exacerbates the decreased effective arterial blood volume, feeding back into the cycle of further activation of the renin–angiotensin system [19]. Adults with hepatorenal syndrome (HRS) are at a higher risk of waitlist mortality.
Nutritional Issues
Malnutrition in cirrhosis results from anorexia, with consequent inadequate calorie and protein intake; malabsorption; steatorrhea; and fat-soluble vitamin deficiencies. Malnutrition is a common complication of liver disease and is particularly relevant in the infant population. Standard measures of weight, height and body mass index underestimate the extent of malnutrition in children, particularly in those with advancing hepatosplenomegaly and ascites; triceps skinfold thickness is a more accurate assessment of nutritional status. Inadequate nutritional intake related to anorexia or the general malaise that accompanies chronic liver disease is further exacerbated by increased metabolic demand. Malabsorption of ingested foods, particularly fats, is also common in advanced liver disease. Deficiencies of fat-soluble vitamins can exacerbate other complications of cirrhosis, such as coagulopathy. Failure of linear growth secondary to chronic malnutrition is often observed in children with advanced liver disease and is associated with poor outcomes both before and after liver transplantation [20].
Orthopedic Manifestations
Hepatic osteodystrophy (liver-associated bone disease) is a significant issue in the pediatric population with chronic liver disease and is related to poor nutrition, malabsorption of vitamin D, and systemic inflammation. Fractures are increasingly common in cirrhotic patients, and patients should be screened for decreased bone mineral density with dual energy X-ray absorptiometry [21].
Evaluation
Evaluation of a patient with liver dysfunction and suspected cirrhosis should focus on determining both the cause and the stage of liver disease. Table 5.4 lists the diagnostic tests that should be considered in evaluating a child with liver disease. Serologic testing for infectious diseases should include screens for hepatitis B and C viruses. In appropriate clinical situations (fever in the setting of previous biliary tree surgery), bacterial cultures of blood and possibly liver tissue can be obtained to assess for cholangitis.
Table 5.4 Diagnostic tests in chronic liver disease and cirrhosis
| Disorder | Diagnostic test |
|---|---|
| Infections | |
| Hepatitis B | Hepatitis B surface antigen, heptatitis B e antigen/antibody, viral DNA with PCR |
| Hepatitis C | Hepatitis C antibody, RNA antigen, viral DNA with PCR |
| Cytomegalovirus | Serology and urine for virus, viral DNA with PCR |
| Epstein–Barr virus | Serology, heterophile antibody |
| Bacterial cholangitis | Blood and liver tissue culture |
| Autoimmune chronic active hepatitis | Anti-nuclear antibodies, anti-smooth muscle antibody, anti-mitochondrial antibody, anti-liver–kidney-microsomal antibody, total IgG level |
| Metabolic disorders | |
| a1-Antitrypsin deficiency | Serum a1 antitrypsin, protein isoelectric focusing |
| Glycogen storage disease | Lactic acid, fasting blood sugar, uric acid, liver and muscle tissue enzyme level |
| Galactosemia | Urinary non-glucose reducing sugar, red blood cell galactose-1-phosphate uridyltransferase level |
| Tyrosinemia | Serum amino acid levels, urine organic acids |
| Neonatal hemochromatosis | Buccal biopsy, MRI for iron deposition in pancreas |
| Cystic fibrosis | Sweat chloride test, genotype analysis |
| Wilson disease | Serum copper, serum ceruloplasmin, 24-hour urinary collection for copper, slit-lamp examination, liver copper concentration, Wilson genetics |
PCR, polymerase chain reaction.
Tests for metabolic liver disease should include quantification of serum α1-antitrypsin with determination of phenotype by protein isoelectric focusing, fasting blood sugar (glycogen storage disease), and sweat chloride test (for cystic fibrosis). Evaluation for galactosemia (urinary reducing substances) and tyrosinemia (serum amino acids with urinary organic acids) could be considered, although these conditions usually present more acutely. In older children, the diagnoses of Wilson disease and autoimmune hepatitis should be considered. The initial evaluation for Wilson disease includes serum ceruloplasmin. Direct sequencing of ATP7B is widely available and is now the standard for molecular diagnosis [22]. Screening for autoimmune hepatitis uses anti-smooth muscle antibody, anti-mitochondrial antibody, anti-liver–kidney-microsomal antibody, and anti-nuclear antibody, as well as total IgG level.
An abdominal ultrasound examination aids in the evaluation of gallstones, choledochal cyst, Caroli disease (cystic dilatation of the intrahepatic biliary tree), and spleen size. A Doppler ultrasound should be done to evaluate the anatomy and blood flow of the hepatic arterial and venous system. In infants in whom the consideration of extrahepatic biliary atresia is paramount, imaging, biopsy and intraoperative cholangiogram has to be considered. In patients with suspected extrahepatic biliary tree obstruction, endoscopic retrograde cholangiopancreatography could provide additional information regarding etiology. The timing of liver biopsy in the investigation of suspected cirrhosis in children remains a matter of clinical judgment. A biopsy may be critical to confirm the presence of cirrhosis suspected on clinical grounds, to verify an etiology, or if the investigations outlined here fail to reveal the cause of the chronic liver disease. Sequencing for genetic disease associated with cirrhosis and chronic liver disease should be considered, as cost can be less prohibitive than invasive procedures and imaging.
Assessment of Liver Function and Prognosis in Cirrhosis
An ideal test of liver function should be able to indicate whether irreversible and potentially fatal changes have occurred early in the patient’s course, and it should be practical and pose minimal risk to the patient. The standard measurements of hepatic function involve a number of tests, few of which actually measure functional capacity of the liver.
Serum Presence of Liver Proteins
The hepatic aminotransferases, aspartate aminotransferase and alanine aminotransferase, are sensitive indicators of hepatocellular injury. These proteins are intracellular enzymes that are normally present in low concentrations systemically but are released from the hepatocyte into the circulation when hepatocellular death occurs. High serum aminotransferase levels suggest acute hepatocellular disease, whereas moderate elevations suggest chronic liver disease. In fulminant hepatic failure, decreasing or low serum aminotransferases can either herald complete destruction of the liver or demonstrate liver recovery. Aspartate aminotransferase is not specific to the liver, and elevations can occur in cardiac disease (myocardial infarction, pericarditis, myocarditis), muscle disease (muscular dystrophy, myositis), and hemolysis (hemolytic anemia or red cell injury caused by traumatic phlebotomy). Alanine aminotransferase is more specific to the hepatocyte. Since aminotransferases in serum are an indicator of hepatocellular injury, the most serious shortcomings are its lack of prognostic value and its inability to quantitatively measure liver function or synthetic capacity.
Hyperbilirubinemia may be associated with hepatocellular dysfunction, the obstruction of bile flow, or extrahepatic diseases such as hemolytic anemia. In obstructive biliary disease, serum alkaline phosphatase and gamma-glutamyltransferase usually are elevated along with bilirubin, because these enzymes are localized in the cellular membranes of canalicular cells. Both of these enzymes are not specific to the liver and can be elevated in other disease processes. In the hepatic disorders of childhood, these tests generally have poor prognostic value; that is, although greatly elevated levels may be associated with poor prognosis, mildly elevated levels provide no reassurance that there is not serious and progressive liver disease.
Investigations that reflect hepatic synthetic capacity are better predictors of survival. Hypoalbuminemia and clotting factor deficiencies have been associated with liver failure, and it has been suggested that decreased synthesis of these proteins by injured hepatocytes is responsible for these deficiencies. Serum albumin concentrations alone are not reliable indicators of liver function or prognosis as they reflect albumin distribution and degradation as well as liver-derived synthesis. Because albumin has a serum half-life of 21 days, serum levels often do not represent current albumin production, particularly in the presence of ascites. Albumin is a component of ascitic fluid, and serum albumin slowly equilibrates with albumin in the ascitic fluid. The liver supplies essentially the entire intravascular pool of albumin and, with progressive ascites, an increasingly large extravascular albumin pool as well. Measurements of albumin synthetic rates have shown normal, decreased, or increased rates of albumin synthesis.
Because of their short half-lives, clotting factors in serum have been studied as indices of liver function, particularly in acute settings. It is generally agreed that increased prothrombin time unresponsive to vitamin K implies poor hepatic synthetic capacity and decompensated hepatocellular disease. Because of its short half-life (six hours), factor VII has been evaluated as a prognostic indicator in acute liver failure. Single determinations of serum factor VII levels are not as helpful as serial determinations over time, since it is a static variable. Low levels of factors V, VII, and XIII or plasminogen are associated with poor prognoses. Studies of serum clotting factor activities are confounded by alterations in the degradation rates of the proteins. The presence of disseminated intravascular coagulation, for example, aggravates the clotting factor deficiency resulting from liver disease. Additionally, the prognostic value of clotting factor levels in early or milder forms of liver disease is not known. Isolated changes in the serum concentration of liver-derived proteins are non-specific (changes may reflect extrahepatic disease) and insensitive (changes may lag behind changes in protein synthesis rates).
Related posts:
Chapter 6 – Portal Hypertension in Children
Chapter 12 – Neonatal Jaundice and Disorders of Bilirubin Metabolism
Chapter 16 – Diseases of the Gallbladder in Infancy, Childhood, and Adolescence
Chapter 26 – Cystic Fibrosis Liver Disease in Children
Chapter 32 – Lysosomal Storage Disorders in Children
Chapter 43 – Liver Transplantation in Children: Indications and Surgical Aspects
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