Pediatric Annals

CME Article 

A Nine-Year-Old Girl with Liver Enlargement

Marilyn Brown, MD; Prita Mohanty, MD; Vibha Sood, MD

Abstract

CME Educational Objectives

  1. Outline the differential diagnosis for liver enlargement.

  2. Describe the findings leading to the diagnosis of primary sclerosing cholangitis in a child.

  3. Describe the association between primary sclerosing cholangitis and inflammatory bowel disease.

A 9-year-old previously healthy girl was noted to have an enlarged liver by the pediatrician during her well-child checkup. No complaints of itching, bruising, bleeding, or appetite loss were noted. There was no history of jaundice, abdominal pain, fevers, or fatigue.

Her past medical history was remarkable for seasonal allergies, constipation, milk intolerance, elevated erythrocyte sedimentation rate (ESR), and peripheral eosinophilia. Upon review of systems, she had no weight loss, fevers, or chills. No unusual skin rash or itching was noted. She had no respiratory, cardiac, or gastrointestinal (GI) symptoms. She had no bowel or bladder incontinence, and there was no history of drug intake. The patient was up to date with all vaccines. Her development and milestones were normal. Family history was significant for maternal grandmother having “spotted liver” and questionable twisted colon per family.

Upon examination, her height and weight were at the 75th and 50th percentile, respectively. Abdominal examination was remarkable for liver edge being palpable 3 to 4 cm below the costal margin, and the spleen tip was palpable as well. No jaundice or skin rash was noted. The remainder of the examination was normal.

Abstract

CME Educational Objectives

  1. Outline the differential diagnosis for liver enlargement.

  2. Describe the findings leading to the diagnosis of primary sclerosing cholangitis in a child.

  3. Describe the association between primary sclerosing cholangitis and inflammatory bowel disease.

A 9-year-old previously healthy girl was noted to have an enlarged liver by the pediatrician during her well-child checkup. No complaints of itching, bruising, bleeding, or appetite loss were noted. There was no history of jaundice, abdominal pain, fevers, or fatigue.

Her past medical history was remarkable for seasonal allergies, constipation, milk intolerance, elevated erythrocyte sedimentation rate (ESR), and peripheral eosinophilia. Upon review of systems, she had no weight loss, fevers, or chills. No unusual skin rash or itching was noted. She had no respiratory, cardiac, or gastrointestinal (GI) symptoms. She had no bowel or bladder incontinence, and there was no history of drug intake. The patient was up to date with all vaccines. Her development and milestones were normal. Family history was significant for maternal grandmother having “spotted liver” and questionable twisted colon per family.

Upon examination, her height and weight were at the 75th and 50th percentile, respectively. Abdominal examination was remarkable for liver edge being palpable 3 to 4 cm below the costal margin, and the spleen tip was palpable as well. No jaundice or skin rash was noted. The remainder of the examination was normal.

A 9-year-old previously healthy girl was noted to have an enlarged liver by the pediatrician during her well-child checkup. No complaints of itching, bruising, bleeding, or appetite loss were noted. There was no history of jaundice, abdominal pain, fevers, or fatigue.

Her past medical history was remarkable for seasonal allergies, constipation, milk intolerance, elevated erythrocyte sedimentation rate (ESR), and peripheral eosinophilia. Upon review of systems, she had no weight loss, fevers, or chills. No unusual skin rash or itching was noted. She had no respiratory, cardiac, or gastrointestinal (GI) symptoms. She had no bowel or bladder incontinence, and there was no history of drug intake. The patient was up to date with all vaccines. Her development and milestones were normal. Family history was significant for maternal grandmother having “spotted liver” and questionable twisted colon per family.

Upon examination, her height and weight were at the 75th and 50th percentile, respectively. Abdominal examination was remarkable for liver edge being palpable 3 to 4 cm below the costal margin, and the spleen tip was palpable as well. No jaundice or skin rash was noted. The remainder of the examination was normal.

Initial work-up at the pediatrician’s office revealed normal white blood cell count and normal hemoglobin levels; platelets were 447,000/μL. Her basic electrolytes were normal. Aspartate aminotransferase (AST) was 216 U/L (normal range, 9–37); alanine aminotransferase (ALT) was 243 U/L (normal range, 12–65); ESR was 81 mm/h (nornal range, 0–15); alkaline phosphatase was 1340 U/L; gamma-glutamyl transpeptidase (GGT) was 583 U/L; total proteins were 8.9 g/L; albumin was 4.3 g/L; total bilirubin was 0.5 mg/dL; C-reactive protein was 7.2 mg/L; prothrombin time (PT) was 14.0 seconds; partial thromboplastin time (PTT) was 3.2 seconds; and International Normalized Ratio (INR) was 1.1. Abdominal ultrasound revealed hepatomegaly (15.7 cm) and splenomegaly (12.0 cm).

The patient was referred to the pediatric gastroenterologist to evaluate for hepatosplenomegaly and transaminitis. Further lab work was ordered and that revealed the following: ceruloplasmin −49 (normal range, 16–45); alpha-1 antitrypsin-190 (normal range, 90–200); hepatic panel for cytomegalovirus (CMV), Epstein-Barr virus (EBV), and hepatitis A, B, and C was negative; anti–double-stranded DNA antibody (anti-dsDNA Ab) was 11 (a value > 10 is mildly positive); antinuclear body antibody (ANA) was negative; total immunoglobulin G (IgG) levels were elevated (with elevated IgG-1, IgG-2, and IgG-4 levels); F-actin antibody was 25 (a value of 0–9 is weakly positive;) antineutrophil cytoplasmic autoantibody (ANCA) was negative; smooth muscle antibody (IgG) was < 1:20; liver-kidney microsomal antibody (LKM Ab) was < 1:20; and mitochondrial antibody was 2.5 units (normal range, 0–20).

Ultrasound Doppler of the abdomen revealed intrahepatic biliary dilatation, mildly dilated common bile duct (CBD), and patent hepatic and splenic vasculature with hepatosplenomegaly. She underwent further magnetic resonance cholangiopancreatography (MRCP) (Figure 1), which showed a kink in the proximal CBD. CBD and hepatic ducts were dilated with beaded appearance of hepatic ducts (Figure 2), no stricture was identified, and no gall bladder stone/sludge was noted.

Kink in the common bile duct.All images courtesy of Vibha Sood, MD. Reprinted with permission.

Figure 1. Kink in the common bile duct.All images courtesy of Vibha Sood, MD. Reprinted with permission.

Beaded appearance of the hepatic ducts.

Figure 2. Beaded appearance of the hepatic ducts.

She later had an ultrasonographic-guided liver biopsy performed, which showed prominent proliferation of the bile ducts in the portal tracts with scattered neutrophils and plasma cells; and bridging fibrosis extending between portal tracts. Periductal onion-skin fibrosis was seen around small- and medium-sized bile ducts (Figure 3).

Periductal onion-skin fibrosis.

Figure 3. Periductal onion-skin fibrosis.

Diagnosis

Primary Sclerosing Cholangitis

For evaluation of a child with liver enlargement, a thorough history and physical examination should be the first step. Hepatomegaly, with elevated liver enzymes, GGT and alkaline phosphatase in the absence of hyperbilirubinemia, should warrant a work-up to rule out Wilson’s disease, autoimmune hepatitis, viral hepatitis, metabolic disorders, primary sclerosing cholangitis, and malignancy.

Discussion

Our patient had normal ceruloplasmin levels serology and viral hepatitis was negative. Autoimmune evaluation did not reveal elevated autoantibodies. Her complete blood count did not show any evidence of underlying malignancy. Liver biopsy and MRCP findings led to the diagnosis of primary sclerosing cholangitis (PSC).

PSC is a chronic cholestatic disorder of unknown etiology, characterized by inflammation and progressive obliterative fibrosis of the intra- and/or extrahepatic bile ducts. It progresses slowly and often asymptomatically to biliary cirrhosis, liver failure, and sometimes cholangiocarcinoma.

The overall incidence of PSC is unknown in children, with the highest number reported from northern Europe. A recent study conducted at University of Calgary showed an incidence rate of 0.23 per 100,000 person-years in children.1 Most cases of PSC show strong association with male gender (62%), white ancestry, and inflammatory bowel disease (IBD). Lifelong risk of PSC increases in first-degree relatives of children and adults with PSC to 0.5%. The genetics of PSC are complex; different human leukocyte antigen (HLA) complexes have been associated with PSC, including HLA-B8 and HLA-DR3.

Pathophysiology of PSC is not well defined; the best described current theory about pathogenesis of PSC is an immune-related destruction of the biliary tree triggered by an infectious agent in a genetically susceptible host, with or without bowel involvement.

The usual age of presentation in children is 7 to 15 years. Most patients have no symptoms and are found incidentally, as was the case in our patient. The classic presentation of jaundice, fatigue, pruritus, and anorexia with concurrent IBD is distinctly uncommon in children. Presenting symptoms and signs may include abdominal pain, diarrhea, fatigue, jaundice, pruritus, weight loss, fever, hepatomegaly, splenomegaly, and ascites. Occasionally, children may present with complications related to portal hypertension, in the form of isolated splenomegaly, variceal bleeding, or an obstructive cholangiopathy.

Sclerosing cholangitis in children can present in the following ways:2

  1. PSC associated with IBD: up to 80% of children with PSC have or will have IBD (most have ulcerative colitis, some may have indeterminate colitis), whereas PSC is diagnosed in up to 4% of children with IBD.

  2. Autoimmune sclerosing cholangitis: sclerosing chonlangitis with strong autoimmune features is referred to as ASC or autoimmune overlap syndrome. Patients present with florid auto-immune features such as elevated ANAs, elevated smooth muscle antibodies (SMAs), and elevated IgG, along with histologic features of interface hepatitis and lymphoplasmacytic infiltration.

  3. Small duct sclerosing cholangitis: this affects the small bile ducts and is often difficult to diagnose by imaging techniques. Diagnosis is made in the setting of biochemical and histologic features.

  4. Neonatal sclerosing cholangitis: approximately 10% of cases present with conjugated hyperbilirubinemia with pale stools in early infancy, then later develop recurrent jaundice and/or hepatosplenomegaly with biochemical, imaging, and histologic findings of PSC.

The diagnosis of PSC is based on a combination of biochemical evidence of biliary disease, with radiologic findings and characteristic histologic changes typical for PSC.3 Elevated serum GGT (which reflects intrahepatic bile duct involvement) with or without elevated alkaline phosphatase (ALP), is a more sensitive marker than alkaline phosphatase level in growing children and reflects intrahepatic bile duct involvement. Children with PSC may also present with elevated serum IgG levels, positive ANAs, and positive anti-SMAs (suggestive of autoimmune sclerosing cholangitis), whereas those with IBD may have positive ANCAs. Complete blood count may reflect hypersplenism, leukopenia, and thrombocytopenia. Most of the patients have intact hepatic function and normal bilirubin levels; however, AST/ALT levels may be raised, as in our patient.

Imaging of the biliary tree is the most important tool in the diagnosis of PSC. Endoscopic retrograde cholangiopancreatography (ERCP) is sensitive but the associated risk of pancreatitis, cholangitis, and hemorrhage is high. MRCP is the most commonly used modality in diagnosis of PSC, as it is noninvasive and does not expose the patient to radiation. MRCP is reported to be 84% sensitive in diagnosing PSC.4 Findings include narrowing and strictures of the CBD, biliary dilatations, and beading of the intrahepatic or extrahepatic biliary tree. Our patient had a kink in the CBD along with beaded appearance of the hepatic duct.

Characteristic histologic changes on liver biopsy include bile duct injury and “onion-skin” type of periductal fibrosis around the medium- and large-sized bile ducts; most children have bridging necrosis at the time of diagnosis. Liver biopsy of our patient (Figure 3) showed prominent proliferation of the bile duct in the portal tract with scattered neutrophils and plasma cells. Bridging fibrosis was noted between portal tracts. Periductal onion-skin fibrosis was seen around small- and medium-sized bile ducts.

Treatment is mainly supportive and directed at managing complications (dominant stricture, pruritus, nutritional deficiencies, and cholangitis) rather than the underlying PSC. Administration of ursodeoxycholic acid (UDCA), the hydrophilic dihydroxy bile acid, results in improvements in serum bilirubin and transaminase levels but has not been proven to prolong overall survival in children. It produces improvement in the symptoms of pruritus. Current recommendations are to start UDCA therapy at a dose of 20 mg/kg per day. In patients with autoimmune overlap, corticosteroids are used along with other immunosuppressant treatment for long-term management. UDCA, antihistamines, rifampin, and cholestyramine have been used to control symptoms of pruritus. Surgical treatment is mainly to manage dominant strictures and to relieve biliary obstruction by utilizing endoscopic techniques such as balloon dilatation and stent placement.

Orthotopic liver transplantation is the only therapy that can reverse or correct end-stage liver disease caused by PSC. The most common indications for transplantation are recurrent cholangitis, cirrhosis with impaired liver function, intractable ascites, variceal bleeding, hepatic encephalopathy, and growth failure. Our patient was started on UDCA, and following that her liver enzymes levels returned to the baseline. She underwent colonoscopy to rule out IBD and biopsy results were normal. She was referred to a pediatric hepatic transplant center for further evaluation regarding liver transplant. PSC is a progressive liver disease that often presents in association with IBD colitis. Serum GGT should be tested in children with chronic hepatitis or whenever PSC is suspected. MRCP is an excellent screening imaging modality for PSC, being noninvasive and without risk of radiation. PSC cannot be ruled out without a liver biopsy. Biochemical improvement is noted with UDCA, but the effect on long-term outcome in children is unclear. Given the natural history of evolution to biliary cirrhosis and cholangiocarcinoma, orthotopic liver transplantation is ultimately required in the majority of patients diagnosed with PSC.

References

  1. Kaplan GG, Laupland KB, Butzner D, Urbanski SJ, Lee SS.. The burden of large and small duct primary sclerosing cholangitis in adults and children: a population-based analysis. Am J Gastroenterol. 2007; 102(5):1042–1049. doi:10.1111/j.1572-0241.2007.01103.x [CrossRef]
  2. Kerkar N, Miloh T. Sclerosing cholangitis: pediatric perspective. Curr Gastroenterol Rep. 2010;12(3):195–202. doi:10.1007/s11894-010-0104-5 [CrossRef]
  3. Miloh T, Arnon R, Shneider B, Suchy F, Kerkar N. A retrospective single-center review of primary sclerosing cholangitis in children. Clin Gastroenterol Hepatol. 2009;7(2):239–245. doi:10.1016/j.cgh.2008.10.019 [CrossRef]
  4. Chavhan GB, Roberts E, Moineddin R, Babyn PS, Manson DE. Primary sclerosing cholangitis in children: utility of magnetic resonance cholangiopancreatography. Pediatric Radiol. 2008;38:868–873. doi:10.1007/s00247-008-0918-6 [CrossRef]

Authors

Vibha Sood, MD, is a Fellow, Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, University of Rochester Medical Center, Rochester, NY. Prita H. Mohanty, MD, is a Fellow, Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, University of Rochester Medical Center, Rochester, NY. Marilyn Brown, MD, is Professor of Clinical Medicine, Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, University of Rochester Medical Center, Rochester, NY.

Disclosure: The authors have disclosed no relevant financial relationships.

Address correspondence to: Vibha Sood, MD, Division of Pediatric Gastroenterology and Nutrition, University of Rochester Medical Center, 601 Elmwood Avenue, Box 667, Rochester, NY 14642; email: Vibha_Sood@urmc.rochester.edu

10.3928/00904481-20120525-09

Sign up to receive

Journal E-contents