STACEY R. ROSE
HISTORY OF PRESENT ILLNESS
The patient is a 12-year-old boy with recent onset of scleral icterus. He was in his usual state of good health until 3 weeks ago, at which time his parents noticed yellowing of his eyes. The patient also complained about itching of his arms and legs. He reported having a good appetite but his parents felt that he was eating smaller meals. His stool output had not changed in quantity or quality; there was no history of bloody or dark stool. Urine output was unchanged. There was no history of abdominal pain, vomiting, diarrhea, anorexia, weight loss, fever, fatigue, bleeding, or easy bruis-ability. There was no joint pain. There was no history of travel, tattooing, or unusual exposures.
The boy was seen in his pediatrician’s office where hepatosplenomegaly was detected. He was referred to the hospital for further evaluation.
The boy had no history of hospitalization, surgery, or chronic medical problems. He was a full-term baby. He takes no medications, has no allergies, and is up-to-date with immunizations. The patient has an aunt with ulcerative colitis but family history was otherwise noncontributory. His three siblings were healthy. The boy was a seventh-grader who liked school and did well there.
T 37.2°C; HR 96 bpm; RR 20/min; BP 110/64 mmHg; Weight 37 kg (5th percentile); Height 144 cm (5th percentile)
Physical examination revealed a smiling, pleasant, and cooperative boy. His examination was notable for mildly icteric sclera. The oropharynx was clear. There was no lymphadenopathy. His lungs were clear with unlabored respirations. Heart examination revealed a regular rate and rhythm with a soft I/VI systolic ejection murmur at the left sternal border; peripheral pulses were normal. The abdomen was soft with mild right upper quadrant tenderness. In addition, there was splenomegaly to the level of the umbilicus and the liver edge was palpable 2 cm below the right costal margin. A rectal examination was normal. On genitourinary examination, he was a Tanner I boy without hernia or scrotal swelling. His extremities were warm and well-perfused without edema. Neurologically he was alert and entirely appropriate with a grossly normal examination. His skin examination revealed only multiple chest nevi and some faint scratch marks on his arms.
Complete blood count: WBCs, 4800/mm3 (segmented neutrophils 41%, lymphocytes 44%); hemoglobin, 12.1 g/dL; platelets, 160 000/mm3. Serum electrolytes, normal. Liver function tests: total bilirubin, 3.0 mg/dL, conjugated bilirubin 2.5 mg/dL; ALT, 176 U/L; AST, 228 U/L; alkaline phosphatase, 565 U/L; gamma glutamyl transferase, 345 U/L. Amylase, 67 U/L, lipase, 178 U/dL. Chest radiograph, borderline cardiomegaly but no infiltrates. Abdominal X-ray, no evidence of bowel obstruction.
COURSE OF ILLNESS
Additional laboratory studies were obtained including the following: erythrocyte sedimentation rate, 80 mm/h; prothrombin time, 12.7 seconds; partial thromboplastin time, 31 seconds. Hepatitis B surface antibody was positive. Hepatitis B surface antigen, hepatitis B core antibody, hepatitis A IgM, and hepatitis C polymerase chain reaction were all negative. Abdominal ultrasound showed an enlarged left lobe of the liver, macronodular changes in the liver parenchyma consistent with cirrhosis, a very enlarged spleen, minimal scattered adenopathy, and dilatation of the left bile duct. The child was admitted to the hospital for further evaluation of his hyperbilirubinemia, cirrhosis, and bile duct dilatation. Endoscopic retrograde cholangiopancreatography (ERCP) demonstrated irregularity and “beading” of portions of the biliary tract, along with dilatation of the left bile duct (Figure 15-9). These characteristic findings suggested the diagnosis.
FIGURE 15-9. Cholangiogram. Note the irregular appearance of the biliary tree with multiple strictures and a “pruned-tree” appearance. (Courtesy of Dr. David Piccoli, The Children’s Hospital of Philadelphia. Philadelphia, PA.)
DISCUSSION CASE 15-5
This boy presented with conjugated hyperbilirubinemia, evidence of liver injury, reflected in the elevation of his transaminases, and left bile duct dilatation. Elevations in conjugated bilirubin, alkaline phosphatase, and GGT levels suggest a cholestatic disorder. The differential diagnosis of cholestatic jaundice in the older child is very different from the list of diseases that present in the first few months of life (Table 15-9). Infants are more likely to have congenital anatomic anomalies (e.g., biliary atresia, cystic malformations) or inborn metabolic disorders (e.g., galactosemia, Zellweger syndrome, bile acid metabolism deficiencies), whereas older children are more likely to experience acquired or secondary liver diseases, such as autoimmune or toxic hepatitis, or liver impairment related to inflammatory bowel disease. Infection is one area where there is broad overlap between the differential diagnoses of both younger and older children. Infectious hepatitis is among the most common causes of liver disease in older children and adolescents (Table 15-9).
TABLE 15-9. Common causes of cholestasis in the older child or adolescent.
Imaging studies revealed left bile duct dilatation, which implies an obstructive, extrahepatic cause of this patient’s conjugated hyperbilirubinemia. Obstructive etiologies to consider in this age group include cholelithiasis, choledochal cysts, sclerosing cholangitis, pancreatitis, and tumors or other anatomic abnormalities along the choledochopancreatico-duodenal path.
Endoscopic retrograde cholangiopancreatography (ERCP) demonstrated irregularity and “beading” of portions of the biliary tract, along with dilatation of the left bile duct (Figure 15-9). An open biopsy of the liver was performed. Tissue pathology revealed cirrhosis, bile duct proliferation, patchy lymphocytic infiltrates, and concentric fibrosis around the bile ducts, confirming the diagnosis of sclerosing cholangitis(Figures 15-10 and 15-11). Additional testing to evaluate for an underlying etiology of his condition was negative, and therefore he was presumed to have primary sclerosing cholangitis (PSC).
FIGURE 15-10. Liver biopsy specimen showing characteristic “onion-skin” fibrosis.
FIGURE 15-11. Liver biopsy specimen showing bile duct proliferation, patchy lymphocytic infiltrates, and concentric fibrosis around the bile ducts.
INCIDENCE AND PATHOPHYSIOLOGY
Sclerosing cholangitis, an inflammatory disease of the hepatobiliary system, is characterized by intra- and extrahepatic bile duct inflammation that progresses to areas of obliteration and dilatation. Sclerosing cholangitis is considered secondary when it occurs in the setting of cholelithiasis, cystic fibrosis, Langerhans histiocytosis, neoplasia (e.g., Hodgkin disease, ductal carcinoma), anatomic abnormalities (e.g., congenital or postsurgical), immunodeficiencies, and chronic ascending infection. Primary sclerosing cholangitis (PSC), however, is diagnosed when no such underlying disease exists.
Primary sclerosing cholangitis is a rare, progressive disease that often results in biliary cirrhosis, portal hypertension, and liver failure. In the year 2000, one study estimated that there were 20.9 cases in 100 000 men and 6.3 out of 100 000 women, though the incidence in children is even lower. PSC is more prevalent in men and has an increased incidence among first-degree relatives. Additionally, there is a strong association between primary sclerosing cholangitis and inflammatory bowel disease (IBD) with ulcerative colitis being prevalent in up to 90% of cases of PSC. However, IBD is not causative. In some cases, the onset of hepatobiliary disease can precede the development of intestinal disease by years, while in others, PSC develops even after proctocolectomy.
The etiology of primary sclerosing cholangitis is not known. Several theories exist, including alterations in immunologic response, bacterial or viral triggers, or ischemia of the biliary tree, although none of these has been proven.
Although primary sclerosing cholangitis can develop at any age, adulthood is the most common period of presentation. Patients may be asymptomatic at diagnosis or may present with malaise, anorexia, abdominal pain, diarrhea, and weight loss. Pruritus is another common symptom of extrahepatic cholestasis, though the precise nature of the pruritogen is not well understood. Frank cholangitis may manifest with right upper quadrant pain, jaundice, and fever.
As PSC progresses, biliary obstruction worsens, secondary biliary cirrhosis develops, and ultimately liver failure ensues. Primary sclerosing cholangitis has an unfavorable prognosis and is a common indication for liver transplantation. PSC is associated with numerous complications, as outlined in Table 15-10, and is a risk factor for colon cancer and cholangiocarcinoma in adults.
TABLE 15-10. Complications associated with primary sclerosing cholangitis.
Children with PSC exhibit many of the same features as their adult counterparts. However, they are more likely to have an overlapping autoimmune hepatitis and tend to have greater elevations in their aminotransferases. Conversely, their risk of developing neoplastic disease is much lower.
Clinical and biochemical evidence of cholestasis may suggest the possibility of PSC, but these findings alone do not differentiate this disease from other entities. Furthermore, the diagnosis of PSC in patients with established Crohn disease or ulcerative colitis can be confounded by the chronic hepatitis that sometimes accompanies inflammatory bowel disease.
Cholangiography. The definitive diagnosis of sclerosing cholangitis is made by cholangiography. Characteristic hepatobiliary changes include strictures, irregular narrowing of bile ducts, and decreased peripheral branching of intrahepatic ducts. Endoscopic retrograde cholangiography has long been considered the study of choice to establish the diagnosis. However, since it is an invasive procedure associated with potentially severe complications like bacterial cholangitis, magnetic resonance cholangiography is often preferred.
Liver biopsy. Liver biopsy is not definitive but may help support the diagnosis. Histologic changes may include the dilatation and obliteration of bile ducts with concentric, periductal “onion skin” fibrosis. Liver biopsy is carried out in staging of the disease and is helpful in determining prognosis.
Unfortunately, management options for PSC are limited. The prognosis in children with PSC is unclear but the 10-year survival rate for adult patients is approximately 65%. There is no known effective medical treatment for primary sclerosing cholangitis. Numerous medications, including corticosteroids and other immunosuppressive agents, have been studied but have not demonstrated a definite benefit. Certain treatments, such as ursodeoxycholic acid (UDCA), may improve symptoms and laboratory abnormalities, but have not been proven to slow progression of disease. Furthermore, a recent study looking at the efficacy of high-dose UDCA in adults, suggested an increased risk of death or liver transplant in patients in the treatment group who had advanced disease. More invasive management may be successful, particularly in patients with dominant biliary tract strictures. Although dominant strictures are rare in children, endoscopic or percutaneous dilatation of the biliary tree can effectively alleviate severe focal obstructions. Surgical resection of the extrahepatic biliary tree and a roux-en-Y hepaticojejunostomy are other options that have been successful in certain patients without cirrhosis. However, since there is continued involvement of the intrahepatic bile ducts, this procedure does not halt disease progression and remains controversial. Liver transplantation is the only effective treatment for PSC patients with progressive liver disease. However, recurrence of disease in the graft is possible.
Given the strong association between PSC and ulcerative colitis, all patients should be evaluated for inflammatory bowel disease with colonoscopy and intestinal biopsies. Nutritional support should be optimized. Adult patients should undergo annual colonoscopy and ultrasound of the gallbladder to screen for colon cancer and cholangiocarcinoma. Since rates of malignancy are significantly lower in children with PSC, it is unclear whether such screening is necessary in the pediatric population, but should be strongly considered in the appropriate clinical setting.
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