Abdominal Pain - Case 7-1: 13-Year-Old Boy
I. History of Present Illness
A 13-year-old boy presented with recurrent abdominal pain. He reported
intermittent right upper quadrant pain for the last year, which occurred two to
three times per week and lasted about 1 hour. The pain was sharp and stabbing
in nature. It was not associated with eating or defecation and did not radiate.
He reported easy bruising, but denied any epistaxis, bloody or tarry stools,
headache, nausea, or vomiting. He did report a 2-month history of tea-colored
urine and a 5-pound weight loss.
II. Past Medical History
His past medical history was unremarkable. He was a full-term infant with no
complications.
III. Physical Examination
T, 37.3°C; RR, 36/min; HR, 80 bpm; BP, 120/77 mm Hg
Height, 75th percentile; weight, 75th percentile
Initial examination revealed an alert and cooperative young man in no acute
distress. Physical examination was remarkable for mild scleral icterus. There
was good lung aeration bilaterally. On abdominal examination, he had
normoactive bowel sounds and tenderness to palpation in the right upper
quadrant. Hepatosplenomegaly was present, with the liver 4 cm below the right
costal margin (with a span of 10 cm) and the spleen 6 cm below the left costal
margin. He was a Tanner stage IV male with normal genitalia and no evidence of
trauma. The skin examination was significant for bruises on the lower
extremities. His neurologic examination was normal.
IV. Diagnostic Studies
Laboratory analysis revealed 3,400 white blood cells (WBCs)/mm3, with 2% band forms, 61% segmented neutrophils, 27% lymphocytes, and 3%
monocytes. The hemoglobin was 12.8g/dL, and there were 51,000 platelets/mm
3. The erythrocyte sedimentation rate (ESR) was slightly elevated at 12 mm/hour.
The hepatic function panel revealed the following: total bilirubin, 2.5 mg/dL;
alkaline phosphatase, 450 U/L; albumin, 2.6 g/dL; and elevated transaminases
(aspartate aminotransferase, 266 U/L; alanine aminotransferase, 162 U/L; and
γ-glutamyltransferase, 500 g/dL). Prothrombin (PT) and partial thromboplastin
(PTT) times were 13 and 32 seconds, respectively. Fibrin split products,
hepatitis A, hepatitis B, hepatitis C, and monospot testing were all negative.
A urinalysis revealed small bilirubin, moderate blood (0 to 2 red blood cells),
and a urobilinogen concentration of 2.0 mg.
V. Course of Illness
The patient was hospitalized and an emergency abdominal ultrasound examination
was performed, which showed portal venous thrombosis with evidence of portal
hypertension, cirrhosis, cholelithiasis, and splenomegaly. There was no
evidence of ascites. An enzyme-linked immunosorbent assay (ELISA) test for
human immunodeficiency virus (HIV) was negative; an antineutrophil cytoplasm
antibody (ANCA) titer was negative; and an antinuclear antibody (ANA) titer was
1:80. Urine copper was elevated at 296
µg/24 hours (normal range, less than 100 µg/24 hours), but ceruloplasmin was within the normal range at 53 mg/dL (normal, 25 to 63
mg/dL). A liver biopsy confirmed the diagnosis (Fig. 7-1).
Discussion: Case 7-1
I. Differential Diagnosis
In the pediatric population, the causes of liver disease, in particular
hyperbilirubinemia and cirrhosis, are diverse. Common causes include infectious
diseases such as viral infections (hepatitis A, B, and C; cytomegalovirus;
coxsackievirus; Epstein-Barr virus), bacterial infections, fungal infections,
and parasitic infections. Inflammatory causes include ulcerative colitis,
ascending cholangitis, and autoimmune hepatitis. Drugs and toxins are another
important cause to explore, because common medications such as acetaminophen
and acetylsalicylic acid and toxins such as iron can cause liver damage. The
differential diagnosis also includes causes of biliary obstruction such as
cholecystitis, cholelithiasis, biliary atresia, arteriohepatic dysplasia
(Alagille syndrome), primary sclerosing cholangitis, fibrosing pancreatitis,
and choledochal cysts. In addition, there is a long and important list of
genetic and metabolic diseases that must be ruled out, which includes cystic
fibrosis,
α1-antitrypsin deficiency, Wilson disease, and several others.
II. Diagnosis
Gross appearance of the liver in a patient with a similar condition revealed
micronodular cirrhosis (Fig. 7-1A). Histologic examination revealed
micronodular cirrhosis with portal
–portal bridging, chronic portal inflammation, and fatty change (Fig. 7-1B).
Rhodanine stain demonstrated copper (red-brown particulate material) within
hepatocytes (Fig. 7-1C). The patient was treated with penicillamine and
pyridoxine. Over the next several months, there were improvements in liver
function and a stable platelet count of 65,000/mm
3. The diagnosis is Wilson disease.
III. Incidence and Pathophysiology
Wilson disease, or hepatolenticular degeneration, was described by Kinnier
Wilson in 1912 as a degenerative disease of the central nervous system with
asymptomatic cirrhosis, but cases were first recognized as early as the 1880s.
Wilson disease is a rare autosomal recessive disorder and is the most common
genetic disorder of copper metabolism. Homozygotes for the disease inherit
mutations of both alleles of the
ATP7B gene on chromosome 13. The incidence is 1 in 500,000 to 1,000,000 births. The
prevalence of homozygotes with disease is approximately 1 in 30,000. The
frequency of heterozygotes (with a single mutation) or carriers is
approximately 1 in 90. The disease is found worldwide, but the rate is higher
among homogeneous, physically isolated, or culturally isolated populations.
Although copper is a vital trace element and coenzyme for several enzymatic
systems, biliary excretion is important to keep the body
's copper load in balance. In Wilson disease, the inherited defect in the biliary
system
's excretion of copper leads to excess copper deposition in the brain, liver, and
other organs. Copper
's toxic effects include generation of free radicals, lipid peroxidation of
membranes and DNA, inhibition of protein synthesis, and altered levels of
cellular antioxidants.
IV. Clinical Presentation
The clinical presentation of Wilson disease is variable, with 42% of patients
presenting with hepatic manifestations, 34% with neurologic disease, and 10%
with psychiatric disease. Although clinical presentation is rare before 5 years
of age, symptomatic cases have been reported. Because initial copper
accumulation occurs in the liver, in the pediatric population hepatic
manifestations usually precede neurologic manifestations. Neurologic symptoms
are more common in the second to third decade of life.
Missed or delayed diagnosis of Wilson disease stems from the nonspecific array
of clinical manifestations. Very young patients who are diagnosed through
family screening or by the incidental finding of Kayser-Fleischer rings on
examination are said to be asymptomatic or presymptomatic. There is also wide
variability in the spectrum of liver disease seen, ranging from asymptomatic
with biochemical abnormalities to acute hepatitis, chronic active hepatitis,
cirrhosis, and fulminant hepatic failure. There is a female predominance (2:1)
of fulminant hepatic failure in Wilson disease. Central nervous system
manifestations include neurologic symptoms (dystonia, tremors, dysarthria, gait
disturbance, choreiform movements) and psychiatric symptoms (poor school
performance, anxiety, depression, neuroses, psychoses). The ophthalmologic
manifestation of the characteristic and diagnostically helpful Kayser-Fleisher
rings is a result of accumulation of copper in the cornea and does not affect
the function of the eye. Other tissues and systems in which copper deposition
does have damaging effects include the endocrine, renal, skeletal, and cardiac
systems. Hemolytic anemia of unclear etiology is a common complication of
Wilson disease and can be the first manifestation of the disease.
V. Diagnostic Approach
The serious sequelae of a delayed diagnosis indicate that Wilson disease should
be seriously considered and investigated in any patient between 3 and 40 years
of age who has any unexplained liver or neurologic disease. This is
particularly important in children and adolescents with extrapyramidal or
cerebellar motor disorders, atypical psychiatric disease, unexplained
hemolysis, and elevated transaminases, either with or without a family history
of liver or neurologic disease. Additionally, individuals who are asymptomatic
but whose family member has confirmed or suspected Wilson disease should be
investigated. Because the classic triad of hepatic disease, neurologic
involvement, and Kayser-Fleischer rings usually is not present in the pediatric
population, a combination of clinical findings, biochemical tests, and
sometimes genetic testing is necessary to establish the diagnosis.
Ophthalmologic examination. Ophthalmic slit-lamp examination of the cornea can demonstrate the
characteristic golden-green granular deposits of Kayser-Fleischer rings in
patients with concomitant neurologic manifestations. Given the presence of
similar corneal rings in other diseases and the frequent absence of
Kayser-Fleischer rings in the pediatric population, their presence or absence
neither confirms nor negates the presence of Wilson disease. In the presence of
neurologic disease, magnetic resonance imaging (MRI) of the brain can delineate
the changes commonly seen in the basal ganglia.
Serum ceruloplasmin. Ceruloplasmin is a serum glycoprotein that is synthesized in the liver and
contains six copper atoms. The mutation in Wilson disease affects this
transport system for copper and leads to decreased incorporation of copper into
ceruloplasmin and decreased circulating levels of copper. Therefore, in Wilson
disease serum ceruloplasmin is decreased. However, low ceruloplasmin levels can
also be seen in other conditions, such as protein-losing enteropathy or
nephrotic syndrome, and even in heterozygotes for Wilson disease. Furthermore,
ceruloplasmin is an acute phase reactant and can be in the normal range in
individuals with Wilson disease. Its production is also induced by hormonal
contraceptives.
Urinary copper. Serum copper levels cannot be used in diagnosis of Wilson disease, but their
determination is helpful in monitoring adherence and response to therapy.
Urinary copper excretion is usually very high (more than 100
µg/24 hours) in symptomatic patients.
Liver biopsy. Currently, liver biopsy with measurement of hepatic copper concentration remains
the mainstay of diagnosis. A liver copper concentration of more than 250
µg/g of dry tissue (five times the normal concentration), in combination with
characteristic histologic findings on light assay or electron microscopy, is
currently considered diagnostic for the disease.
Other studies. In settings in which histologic findings cannot be confirmed, stable copper
isotope studies have replaced radioisotope studies for the determination of
copper metabolism. The test is helpful only in patients with normal serum
ceruloplasmin levels. The genetic heterogeneity of the condition makes the
available DNA studies unhelpful diagnostically unless there is a family member
in whom Wilson disease has been diagnosed and confirmed.
VI. Treatment
Therapy should be initiated immediately after confirmation of the disease and
continued for the remainder of the patient
's life. The goal of therapy is to eliminate symptoms and prevent disease
progression. The armamentarium of treatment includes dietary measures,
pharmacologic therapy, and liver transplantation.
Although a low-copper diet does not play a large role in the treatment of the
disease, it is important for patients to avoid heavy copper-containing foods
such as shellfish, nuts, and chocolate.
Penicillamine, an orally administrated copper chelator, decreases the body's pool of copper by increasing urinary copper excretion and can effectively
reduce or eliminate the effects of copper toxicity. The antipyridoxine effects
of penicillamine necessitate concomitant administration of pyridoxine three
times a week. The dose can be increased if there is no clinical improvement or
decrease in excretion of urinary copper. Adherence to therapy is followed with
measurement of either urinary or serum copper and serum ceruloplasmin. Side
effects are more common with higher doses. Sensitivity reactions, which include
fever, rash, leukopenia, thrombocytopenia, and lymphadenopathy, occur in 10% of
patients but can often be overcome with gradual reinstitution of the
medication. Penicillamine has consistently shown the successful results, with
improvement in liver biopsy findings over time.
Trientine hydrochloride is an alternative chelating agent, particularly for
patients with side effects such as nephrotoxicity and lupus-like syndrome from
penicillamine. Although there is less urinary copper excretion with this agent,
it appears to be equally effective clinically. Iron deficiency or sideroblastic
anemia can be seen. Administration of zinc salts three times daily seems to
protect hepatocytes by inducing metallothionein in enterocytes, which blocks
the intestinal absorption of copper. Sometimes, British antilewisite
(dimercaprol) is the only effective agent; it can be particularly helpful in
patients with progressive neurologic disease that is unresponsive to treatment
with penicillamine, trientine, or zinc.
The indications for liver transplantation in patients with liver disease include
acute hepatic failure (especially in association with hemolysis), advanced
cirrhosis with decompensation, hepatic insufficiency that progresses in the
face of adequate treatment with chelation therapy, and progressive and
irreversible neurologic disease (even in the absence of severe hepatic
disease). Patients receiving liver transplants display total reversal of the
biochemical abnormalities they had previously. Survival rates are variable but
have been reported as high as 79% at 1 year.
Future directions of treatment include gene therapy, but presently early
detection and chelation therapy are still the most important aspects of
treatment.
VII. References
1. Tunnessen WW. Jaundice. In: Tunnessen WW, ed. Signs and symptoms in pediatrics, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 1999:102–112 and 440–447.
2. Chitkara DK, Pleskow RG, Grand RJ. Wilson disease. In: Walker WA, Durie PR,
Hamilton JR, et al., eds.
Pediatric gastrointestinal disease, 3rd ed. Hamilton, Ontario: BC Decker, 2000:1171–1184.
3. Pearce JM. Wilson's disease. J Neurol Neurosurg Psychiatry 1997;63:174.
4. Robertson WM. Wilson's disease. Arch Neurol 2000;57:276–277.
5. Schilsky ML, Tavill AS. Wilson's disease. In: Schiff ER, Sorell MG, Maddrey WC, eds. Schiff's diseases of the liver, 8th ed. Philadelphia: Lippincott–Raven Publishers, 1999:1091–1106.
6. Gaffney D, Fell GS, O'Reilly DS. Wilson's disease: acute and presymptomatic laboratory diagnosis and monitoring. ACP
Best Practice No. 163.
J Clin Pathol 2000;53:807–812.
7. Sternlieb I. Wilson's disease. Clin Liver Dis 2000;4:229–239.
8. Wilson DC, Phillips MJ, Cox DW, et al. Severe hepatic Wilson's disease in preschool-aged children. J Pediatr 2000;137:719–722.
9. Balistreri WF. Wilson disease. In: Behrman RE, et al., eds. Nelson's textbook of pediatrics, 16th ed. Philadelphia: WB Saunders, 2000.
10. Khanna A, Jain A, Eghtesad B, et al. Liver transplantation for metabolic
liver diseases.
Surg Clin North Am 1999;79:153–162.
11. Durand F, Bernuau J, Giostra E, et al. Wilson's disease with severe hepatic insufficiency: beneficial effects of early
administration of D-penicillamine.
Gut 2001;48:849–852.
Pictures
Book Source Details
- Book Title: Pediatric Complaints and Diagnostic Dilemmas
- Author(s): Samir S Shah MD; Stephen Ludwig MD
- Year of Publication: 2003
- Copyright Details: Pediatric Complaints and Diagnostic Dilemmas, Copyright © 2003 Lippincott Williams & Wilkins.
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Copyright Details: Pediatric Complaints and Diagnostic Dilemmas, Copyright © 2008 Williams & Wilkins.
More About Causes of Lower abdominal pain
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