Pediatric Annals

Special Issue Article 

Hepatobiliary Manifestations in Systemic Disease

Joseph Runde, DO; Ruba K. Azzam, MD

Abstract

Liver disease in children occurs via a multitude of primary illnesses such as autoimmune hepatopathy, biliary atresia, and nonalcoholic fatty liver disease. However, jaundice, hepatitis, and alterations in liver tests can often be a manifestation of systemic diseases. The liver is involved in many critical functions such as circulation, immunity, toxin clearance, and metabolism; when the heart, lungs, gastrointestinal tract, immune system, or endocrine systems are compromised, the liver will be affected. This article reviews common causes of liver injury as well as highlights key associations that should not be missed when diagnosing and managing children with liver disease. Becoming familiar with patterns of liver injury and arranging clues in the context of a thorough history and physical examination can help providers navigate the broad differential diagnosis of secondary liver disease. [Pediatr Ann. 2018;47(11):e458–e464.]

Abstract

Liver disease in children occurs via a multitude of primary illnesses such as autoimmune hepatopathy, biliary atresia, and nonalcoholic fatty liver disease. However, jaundice, hepatitis, and alterations in liver tests can often be a manifestation of systemic diseases. The liver is involved in many critical functions such as circulation, immunity, toxin clearance, and metabolism; when the heart, lungs, gastrointestinal tract, immune system, or endocrine systems are compromised, the liver will be affected. This article reviews common causes of liver injury as well as highlights key associations that should not be missed when diagnosing and managing children with liver disease. Becoming familiar with patterns of liver injury and arranging clues in the context of a thorough history and physical examination can help providers navigate the broad differential diagnosis of secondary liver disease. [Pediatr Ann. 2018;47(11):e458–e464.]

We commonly consider abnormal liver chemistry panels in children as stemming from primary liver diseases such as viral hepatitis, autoimmune hepatitis, drug-induced liver injury, or nonalcoholic fatty liver. However, recognizing that the liver is a complex and critical organ tied to vital processes such as circulation, immunity, metabolism, and toxin clearance we can appreciate that hepatitis, jaundice, and abnormal liver biochemistry markers are often hepatobiliary manifestations of systemic illness.

Some patterns of liver injury will appear “hepatocellular,” reflecting a disproportionate elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) over alkaline phosphatase. Others will be more consistent with “cholestatic” injury in which alkaline phosphatase is increased above ALT and AST. This may be supported by elevated gamma-glutamyl transferase. Conjugated bilirubin elevations can be seen in both hepatocellular and cholestatic disease. This article explores important causes of secondary liver disease in children (Table 1).

Hepatobiliary Manifestations in Systemic Disease

Table 1:

Hepatobiliary Manifestations in Systemic Disease

Cardiovascular Disease

The liver is perfused via dual blood supply: the portal vein (deoxygenated, low pressure, and nutrient-rich) and the hepatic artery (oxygenated and high pressure). The liver has a unique capacity to increase hepatic arterial blood flow when portal venous flow has been compromised. However, if the hepatic artery flow is compromised, the central zones of the hepatic lobules will suffer damage as blood is increasingly oxygen depleted as it moves from zone 1 (portal triad) to zone 3 (central vein). The biliary tree is also supplied by the hepatic artery, making it vulnerable to such compromise.

Ischemic Hepatitis

Ischemic hepatitis is characterized by a severe hepatocellular pattern of injury (often greater than 20 times normal) occurring within 1 to 2 days of insult. This may be seen in conjunction with jaundice and coagulopathy. Once the underlying disturbance is corrected, aminotransferase elevation should rapidly decrease by as much as 50% in 2 to 3 days. This may be followed by a slow rise in direct bilirubin that may peak more than 1 week after initial insult.1,2

Hepatic Passive Congestion

In children, the most common reason for heart failure is congenital heart diseases such as pulmonary atresia, truncus arteriosus, tetralogy of Fallot, ventricular septal defect, and transposition of the great arteries.5 Other diseases that may result in chronic liver congestion include pericarditis, restrictive lung disease, and pulmonary hypertension. Mechanisms of damage occur via decreased cardiac output, splanchnic vasoconstriction (renin-angiotensin A system), increased pressure in sinusoids, and increased endotoxin production in the congested intestine.2 Laboratory findings are predominantly cholestatic with elevated alkaline phosphatase and gamma-glutamyltransferase. Histologically, broad fibrous septa will form, which is commonly called “nutmeg liver,” designating cardiac cirrhosis.

Hepatic Venous Outflow Obstruction

Budd-Chiari Syndrome

Obstruction at the small hepatic veins all the way to the inferior vena cava and right atrium is called Budd-Chiari syndrome. This can be primary (as in the case of vascular thrombosis) or secondary (obstruction due to abscesses, cysts, or tumors). The most common cause in developed countries is hepatic vein thrombosis, often occurring as a result of coagulopathy and endothelial injury. Examples of predisposing conditions resulting in hepatic vein thrombosis include factor V Leiden mutation, proteins C and S deficiency, hyperhomocysteinemia, thrombophilia, and antiphospholipid/anticardiolipin antibody disorder. Although the presentation in children may be subtle with minimal signs on physical examination, patients often present with rapid development of abdominal distension and pain, hepatomegaly, and ascites. Biochemical findings can reflect mild hepatocellular or cholestatic inflammation; however, fulminant disease can also be seen at presentation. Evaluation starts with a Doppler abdominal ultrasound, and is confirmed by magnetic resonance imaging or rarely hepatic venography. Treatment focuses on addressing the underlying disease and anticoagulation therapy. Reestablishing hepatic venous flow sometimes requires interventional procedures like venoplasty with stent placement, or even surgical resection of obstruction and portosystemic shunting. Patients with long-standing obstruction culminating in cirrhosis should be referred for evaluation for liver transplantation.

Gastrointestinal Disease

Inflammatory Bowel Disease

Transient elevations of liver tests are frequently seen in patients with inflammatory bowel disease (IBD). The incidence of elevated liver enzymes in patients with IBD is reported to be as high as 40% with almost 90% of cases being idiopathic.3 The most common pattern of liver injury is hepatocellular (69%) with mixed (23%) and isolated cholestatic (8%) being much less common.3

However, it is important to recognize that significant overlap exists between patients with IBD and primary liver disease such as autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC) or the combination of the two, and autoimmune sclerosing cholangitis (ASC). AIH has been reported in up to 1.6% of patients with IBD, 80% of patients with PSC, and ASC is seen in 45% of children with IBD.4 This highlights that persistent abnormal liver biochemistries in patients with IBD must be evaluated for comorbid liver disease.

Celiac Disease

Liver abnormalities may be seen in more than 50% of those presenting with celiac disease (CD).5 In fact, elevated aminotransferases may be the initial presentation of CD in 25% of children. Biochemical patterns should return to normal within 6 months of starting a gluten free diet; if this is not observed, investigation into other causes of liver dysfunction should be undertaken.

Autoimmune hepatopathies have been reported in patients with CD with an incidence of 6.3%, including AIH, PSC, and ASC.6 Nonalcoholic steatohepatitis is also seen in patients with CD; a pathogenetic link has been proposed between nonalcoholic fatty liver disease (NAFLD) and CD involving gut permeability, microbiota, and diet, but the pathogenesis of liver steatosis in CD remains unclear.7

Nutritional Disorders

Malnutrition

In states of caloric deprivation, the body shifts to catabolism, glycogen stores are depleted, and ketones are used as fuel. Eventually proteolysis of muscle and lipolysis of adipose tissue ensue. Free fatty acids are transported to the liver and hepatic steatosis occurs. Kwashiorkor is a state of protein malnutrition associated with severe edema. In this condition, splenomegaly is often seen in addition to significant steatosis. Although it is more common in developing nations, it can also result from dietary inadequacies, particularly when milk and formula are replaced with inappropriate substitutes.5 Marasmus is a state of complete calorie deprivation in which steatotic hepatomegaly is also seen. Aminotransferase elevation is seen in children with eating disorders.8 Most cases of liver injury secondary to malnutrition will resolve rapidly with correction of the underlying problem.

Total Parenteral Nutrition

Liver disease associated with total parenteral nutrition (TPN) develops in 40% to 60% of infants who require chronic TPN related to intestinal failure.9 Chronic cholestasis is observed in more than 50% of patients on TPN for greater than 2 years.10 Patients on long-term TPN will also be subject to the development of gallstone and sludge formation. As injury becomes chronic, this may lead to steatosis, fibrosis, and eventual liver failure.

Dietary Supplements

Dietary supplements are particularly popular in Western culture and are used frequently in children with chronic medical conditions.11 Hepatic presentation may range from asymptomatic elevation in the liver chemistry panel to chronic hepatic injury and cirrhosis and even acute liver failure. One of the most described liver toxicities is hypervitaminosis A;12 however, other potentially toxic supplements include green tea extracts, senna, germander, Japanese herbals, and usnic acid.5

Infectious Disease

In response to infection or inflammation, the liver increases production of acute phase reactants (such as fibrinogen, C-reactive protein, complement factors, haptoglobin, ceruloplasmin), and endotoxins.5 This response attempts to minimize tissue damage, promote repair mechanisms, and combat invading pathogens. However, unintended consequences include leukocytosis, fever, altered mental status, muscle weakness, altered metabolism, insulin resistance, and cholestasis.5 Damage from infection tends to be reversible, rarely progressing to liver failure.

Sepsis

Sepsis, even in the absence of shock, may result in hepatic injury. The classical finding is cholestasis out of proportion to hepatocellular changes. Cholestasis in this setting is often seen in the context of gram-negative bacteremia; however, any infection can result in this picture. Cholestasis develops as a result of impaired hepatocyte/cholangiocyte transport mechanisms, alterations in microvasculature due to congestion, and neutrophilic sequestration.5

Bacterial

Tuberculosis. Liver disease is seen in patients with Mycobacterium tuberculosis and in other mycobacterium species such as M. avium. Patients may present with hepatomegaly and nonspecific biochemical evidence of liver inflammation. Caseating granulomas may be seen in the parenchyma of the liver.

Lyme disease. Reports describe early uptrends in liver chemistries in patients with Lyme disease, particularly in those with disseminated disease (66%).13 Biochemical alterations mostly resolve with adequate treatment of Lyme disease.

Viral

Acute viral hepatitis may present with dramatic elevations in aminotransferase levels, often greater than 25 times normal. When the infection is chronic, elevations are mild. Viral injury may also present with intrahepatic cholestasis, so a high suspicion should be maintained when other causes of liver injury are not ruled out. Viral infection is an important cause of pediatric acute liver failure as viral infections are confirmed in 20% of pediatric acute liver failure cases.14

Hepatitis

Hepatitis A spreads through fecal-oral transmission. The infection may be clinically undetectable or may present as an acute viral illness or even as fulminant liver failure (especially in developing countries). Drastic aminotransferase elevation may be seen that may precede the onset of symptoms. Most children are anicteric with only 10% younger than age 6 years developing jaundice; this percentage increases dramatically with age.15

Hepatitis B and C is spread through contact with blood, other bodily fluids, use of infected needles, and vertical transmission. Liver chemistry abnormalities tend to be mild especially if longstanding injury is present. Hepatitis B leads to chronic liver disease in up to 90% of children infected during infancy, compared to 5% in those infected during adolescence and adulthood.16 This contrasts with 70% to 80% in patients infected with Hepatitis C at any age.16

Herpes simplex virus. Herpes simplex virus (HSV) is most commonly seen in neonates and infants and can lead to necrotic hepatitis and fulminant hepatic failure. In fact, in the pediatric acute liver failure (PALF) registry, HSV was identified as the cause of liver failure in 25% of cases ages 0–6 months of life.17 Early institution of acyclovir is recommended.

Epstein-Barr virus. Acute Epstein Barr virus hepatitis is often benign and self-limited, although high fevers may be recurrent for days to weeks. Aminotransferase levels may rise to 5 times the normal limit or more before returning to normal over the course of a few weeks. Alkaline phosphatase and gamma glutamyl transferase levels may also spike yet anicteric cholestatic liver disease is more common (59%) compared with icteric disease (6%).18

Cytomegalovirus. Most children infected with cytomegalovirus (CMV) are asymptomatic or present with a mild mono-like illness. A special population includes those who are immunocompromised and recipients of organ or stem cell transplantation (SCT) who may develop a severe clinical course. Patients who are immunocompromised are treated with anti-CMV therapy, mainly ganciclovir or valganciclovir.

Fungal infection. Fungal infections, most commonly Candida species, often involve the liver. Pathogenesis of liver involvement stems from colonization of the gastrointestinal tract with translocation to the liver.19 This occurs more frequently in immunocompromised patients, especially if neutropenia is present, and may result in cholestatic injury with the formation of abscesses (oncology patients) or granulomas.

Hematology/Oncology

Hemoglobinopathies

Hepatobiliary disease is frequently seen in patients with hemoglobinopathy. Perhaps the most common feature is cholelithiasis, resulting from accelerated hemolysis and increased bilirubin secretion. This places these patients at risk for biliary tree obstruction and biliary pancreatitis. In one pediatric cohort, 50% of children with hemoglobin SS disease were found to develop gallstones over time, compared with 15% of patients with hemoglobin SC disease.20

Additionally, hepatic vaso-occlusive crises are also common. In extreme cases, patients with sickle cell may present with acute right upper quadrant pain, hepatomegaly, jaundice, and a fall in hemoglobin due to acute hepatic sequestration. Sickle cell intrahepatic cholestasis should be suspected when patients with sickle cell present with dramatically elevated conjugated bilirubin levels (total bilirubin level >13 mg/dL or much higher) and renal insufficiency. Treatment includes exchange transfusion and supportive care. Chronic liver disease may evolve due to microvascular obstruction, infarction, and recurrent scarring. Cirrhosis may be exacerbated in children receiving chronic blood transfusions secondary to hemosiderosis and/or concomitant viral infections.

Oncology

Liver disease may be seen at presentation in children with leukemia, lymphoma, and intra-abdominal solid tumors due to infiltration, obstruction, or secondary to medication toxicity (as with 6-mercaptopurine or methotrexate).

Complications of stem cell transplant. Liver complications are frequent in this population and should be triaged according to timing (pre versus post-transplant) and based on etiology (primary disease, drug-induced, vascular, infection, or iatrogenic-parenteral nutrition).

Sinusoidal obstruction syndrome. Also known as veno-occlusive disease (VOD), sinusoidal obstruction syndrome (SOS) is defined by acute weight gain from edema, tender hepatomegaly, and hyperbilirubinemia in children following SCT, especially in the setting of myeloablative conditioning. Toxic injury to epithelial cells leads to obstruction of terminal hepatic venules in the central lobules of the liver, resulting in outflow blockage. A meta-analysis reports an incidence of around 14%.21 Onset is typically within 30 days of transplantation and may occur soon as 10 days in those receiving regimens with cyclophosphamide. Conducting a Doppler abdominal ultrasound may support the diagnosis. Findings may include reversal of portal flow, decreased hepatic vein flow, and increased resistance in the hepatic artery but they are not always specific. Treatment of SOS is supportive and includes maintaining intravascular volume and paracentesis when significant ascites is present. Medication regimens vary from center to center; however, increasing use of defibrotide, an anti-inflammatory/antithrombotic agent, has been seen. Other common agents may include prophylactic heparin and ursodeoxycholic acid. Most patients who are appropriately supported will recover from VOD.

Graft versus host disease. Acute graft versus host disease GvHD occurs within 100 days of SCT and may affect as many as 50% of stem cell recipients. It is characterized by involvement of skin, intestine, and the liver. Hepatic disease may present with jaundice, hepatomegaly, and elevated liver biochemical markers (particularly alkaline phosphatase and gamma-glutamyltransferase). When in doubt liver biopsy revealing bile duct damage, atypia, pericholangitis, endothelilitis of portal/central veins, and lymphocytic inflammation may confirm the diagnosis.

Chronic GvHD occurs more than 100 days post-transplant and can present in an asymptomatic child with elevated liver chemistry, indolent cholestasis, or acute hepatitis. Histology may be similar to acute GvHD but is more likely to reveal chronic changes such as bile duct proliferation, bridging fibrosis, and/or vanishing bile ducts. Management of GvHD is focused primarily on prevention via adequate immunosuppression. Standard therapy after diagnosis includes corticosteroids, but resistant disease may require calcineurin inhibitors and sometimes biologic agents. Ursodeoxycholic acid is commonly used for its reported22 benefit in the prevention of transplant-related complications in SCT. Severe GvHD may require liver transplantation when medical therapy fails; survival post-liver transplantation is lower than that for other indications at 76% and 69%, respectively, 1 and 5 years later.23

Rheumatologic/Immunologic

Juvenile Idiopathic Arthritis

Patients with juvenile idiopathic arthritis (JIA) may experience transient, intermittent elevations in liver biochemistries that often correlate to underlying disease activity. These abnormalities are not likely to persist or lead to permanent liver injury.5 Although comorbid autoimmune hepatitis may be seen, overlap in diagnostic criteria for autoimmune hepatitis can make distinguishing the nature of abnormal liver laboratories difficult.24

Drug toxicity is the most common reason for an altered liver profile. Methotrexate, a disease-modifying agent, is associated with benign, acute hepatocellular laboratory elevation and rarely insidious hepatic fibrosis. Biologic agents are also used in mainstream therapy and may result in hepatocellular injury and require dose adjustment. In cases of patients systemically ill with JIA with severe liver dysfunction, macrophage activation syndrome should be considered. This entity is generally considered an acquired form of hemophagocytic lymphohistiocytosis, which requires enhanced immunosuppression.

Systemic Lupus Erythematosus

Approximately one-third of patients with systemic lupus erythematosus (SLE) will have biochemical elevation of liver chemistries, and approximately 40% will have appreciable hepatomegaly.25 Patients with SLE may develop medication-induced hepatitis, fatty liver disease, or autoimmune hepatitis. Anti-ribosomal P antibody positivity is more commonly seen in lupus-associated hepatitis compared to autoimmune hepatitis, and could be helpful for distinguishing the two entities, which is important because the former rarely requires targeted therapy.26

The liver may be involved in neonatal SLE. The process results from transplacental passage of maternal anti-Ro/La antibodies resulting in heart block, dermatitis, hematologic derangement, and transient liver involvement in up to 25% of cases. Treatment involves addressing potential heart block and supportive care.

Endocrine Disease

Hypopituitarism

It is believed that adrenocorticotropic hormone and thyroid-stimulating hormone play a role in the regulation of bile acid secretion and flow. Neonatal hepatitis is commonly seen in patients with congenital panhypopituitarism. Addressing the underlying hormone deficiency is all that is needed to resolve the nonspecific inflammatory process in the liver and normalization of hepatic biochemistry.

Adrenal Insufficiency

Adrenal insufficiency, particularly in neonates, may result in elevated aminotransferases, with milder cholestasis being seen. It is important to address the deficiency to prevent long-term consequences to the liver such as nonalcoholic fatty liver with rapid progression to steatohepatitis and cirrhosis.27

Thyroid Disease

As mentioned above, thyroid hormones play a key role in the regulation of bile acid secretion and flow. Liver injury is often present in a hyperthyroid state and may present with hepatocellular injury in 27% to 37% of cases.5 Cholestatic abnormalities may also be seen. In hypothyroidism, UDP-glucuronyl transferase activity is often diminished leading to decreased bilirubin excretion, resulting in mild jaundice. In addition, hypothyroidism is a risk factor for NAFLD development.28

Diabetes Mellitus

Liver dysfunction may be evident in one-third of patients with diabetes mellitus. The spectrum of hepatic involvement includes increased glycogen deposition, steatosis, fibrosis, and even cirrhosis. NAFLD has been reported in patients with diabetes.5

Metabolic Diseases

Although this major entity is important to consider in the setting of liver dysfunction and may present with acute liver failure, particularly in infancy, this topic requires its own in-depth review.

Other

Heat Stroke

The liver is especially vulnerable to thermal injury and elevation of ALT is the most frequent abnormality seen in cases of heat stroke. If rhabdomyolysis is a feature of illness, transaminitis may not be reflective of liver injury but rather muscle injury.29

Myopathy Resembling Liver Disease

Exclusive elevation in serum aminotransaminases could be related to primary muscle disease rather than liver pathology. Elevated creatinine phosphokinase levels can distinguish between both entities and prevents unnecessary testing.

Conclusions

The causes of liver dysfunction in the context of systemic diseases are many, and presentations range from asymptomatic biochemical abnormalities to fulminant liver failure. Although consultation with a pediatric hepatologist may often be necessary in evaluation, maintaining a wide differential diagnosis and using history to help direct care is important for clinicians managing children with evidence of liver abnormalities.

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Hepatobiliary Manifestations in Systemic Disease

Category Etiology More Common Pattern of Injury and Associations
Cardiovascular Ischemic hepatitis (acute): infection, obstruction Hepatocellular>>>cholestatic (delayed)1,2
Hepatic congestion (chronic): congenital heart disease, chronic lung disease, pulmonary hypertension Cholestatic>>hepatocellular5
Obstruction: Budd-Chiari syndrome, SOS Range of mild to severe liver biochemical abnormalities5
Gastrointestinal Inflammatory bowel disease Hepatocellular or cholestatic or both; association with autoimmune hepatopathy3
Celiac disease Hepatocellular >cholestatic; may be presenting sign in 50%; association with autoimmune hepatopathy5,6
Nutrition Malnutrition: kwashiorkor, marasmus, eating disorders Hepatocellular (steatosis)5,8
Parenteral nutrition dependence Most commonly cholestasis ± gall stone formation/sludge, steatosis, and eventual fibrosis or cirrhosis9
Dietary supplements: weight loss supplements, hypervitaminosis Often asymptomatic hepatocellular injury but may result in acute liver failure5,12
Infectious Sepsis/septic shock Cholestatic>>hepatocellular (especially with gram-negative bacteremia); septic shock may result in ischemic hepatitis and severe hepatocellular injury5
Bacterial: tuberculosis, Lyme disease Nonspecific hepatocellular inflammation, granulomas (tuberculosis)13,30
Viral sources: acute viral hepatitis, HSV, EBV, CMV, HIV Hepatocellular >>> cholestatic14–18
Fungal sources Cholestatic if associated with hepatic abscess formation; immunocompromised patients19
Hematology/oncology Hemoglobinopathy Cholestatic often with gallbladder sludge/stones;20 severe in cases of hepatic sequestration31
Oncology: ALL/AML Mild hepatocellular to acute liver failure; consider medication toxicity5
Stem cell transplant: SOS and GvHD SOS: cholestatic;21 acute or chronic GvHD: cholestatic; chronic GvHD associated with vanishing bile duct syndrome (severe cholestasis)22
Rheumatology Juvenile idiopathic arthritis Hepatocellular; consider medication toxicity5,24
Systemic lupus erythematosus Hepatocellular; consider medication toxicity and association with autoimmune hepatopathy25,26
Endocrinology Hypopituitarism Nonspecific hepatocellular or cholestatic5
Adrenal insufficiency Cholestasis (mild), hepatocellular; uncorrected may progress to steatosis/fibrosis (NASH)27
Thyroid disease Hepatocellular or cholestatic; association with NAFLD28
Diabetes mellitus Hepatocellular; associated with NAFLD5
Other Heat stroke Hepatocellular; consider rhabdomyolysis29
Myopathy Hepatocellular-like (transaminitis of muscle origin); check creatinine phosphokinase level32
Authors

Joseph Runde, DO, is a Pediatric Gastroenterology Fellow, Section of Pediatric Gastroenterology, Hepatology and Nutrition, The University of Chicago Medical Center. Ruba K. Azzam, MD, is an Associate Professor of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition; the Director, Pediatric Hepatology; and the Medical Director, Pediatric Liver Transplantation, The University of Chicago Medical Center.

Address correspondence to Ruba K. Azzam, MD, Department of Pediatrics, Section of Gastroenterology, Hepatology, and Nutrition, The University of Chicago Medical Center, 5837 S. Maryland Avenue, MC 4065, Chicago, IL 60637; email: razzam@peds.bsd.uchicago.edu.

Disclosure: Ruba K. Azzam reports speaker fees received from Alexion Pharma. The remaining author has no relevant financial relationships to disclose.

10.3928/19382359-20181023-01

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