HISTORY OF PRESENT ILLNESS
The patient was a 13-year-old male with a medical history significant for recurrent abdominal pain. The patient reported intermittent right upper quadrant pain during the last year. It occurred two to three times per week and lasted about 1 hour. It 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, and nausea or vomiting. He did report a 2-month history of tea-colored urine and a 5-pound weight loss.
His medical history was unremarkable. He was a full-term infant with no complications.
T 37.3°C; RR 36/min; HR 80 bpm; BP 120/77 mmHg
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 on abdominal examination 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.
Laboratory analysis revealed 3400 WBCs/mm3 with 2% bands, 61% segmented neutrophils, 27% lymphocytes, and 3% monocytes. The hemoglobin was 12.8 g/dL and there were 51 000 platelets/mm3. The erythrocyte sedimentation rate was slightly elevated at 12 mm/h. The hepatic function panel revealed a total bilirubin of 2.5 mg/dL; alkaline phosphatase, 450 U/L; albumin, 2.6 g/dL; and elevated transaminases with an aspartate amino-transferase, 266 U/L; alanine aminotransferase, 162 U/L; and a gamma-glutamyl transferase, 500 g/dL. Prothrombin (PT) and partial thromboplastin (PTT) times were 13 and 32 seconds, respectively. Fibrin split products, hepatitis A, B, C, and monospot testing were all negative. A urinalysis revealed small bilirubin, moderate blood (0-2 RBCs), and a urobilinogen of 2.0 mg.
COURSE OF ILLNESS
The patient was hospitalized and an emergent abdominal ultrasound was performed that showed portal venous thrombosis with evidence of portal hypertension, cirrhosis, cholelithiasis, and splenomegaly. There was no evidence of ascites. HIV ELISA was negative, ANCA was negative, and ANA was 1:80. Urine copper returned elevated at 296 μg/24 hours (normal range < 50 μg/24 hours), but the ceruloplasmin was within normal range at 53 mg/dL (range 25-63). A liver biopsy confirmed the diagnosis.
DISCUSSION CASE 7-1
The causes of liver disease, in particular hyper-bilirubinemia and cirrhosis, in the pediatric population are diverse. Common causes include infectious diseases such as viral infections (hepatitis A, B, and C; cytomegalovirus; coxsackie virus; 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 etiology to explore as common medications such as acetaminophen and acetylsalicylic acid and toxins like 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. There is a long and important list of genetic and metabolic diseases that must be ruled out and includes cystic fibrosis, alpha-1-antitrypsin deficiency, Wilson disease, and several others.
Gross appearance of the liver in a patient with a similar condition revealed micronodular cirrhosis (Figure 7-1A). Histologic examination revealed micronodular cirrhosis with portal-portal bridging, chronic portal inflammation, and fatty change (Figure 7-1B). Rhodanine stain demonstrated copper (red-brown particulate material) within hepatocytes (Figure 7-1C). The patient was treated with penicillamine and pyridoxine. During the next several months, there were improvements in liver function and a stable platelet count of 65 000/mm3. The diagnosis is Wilson disease.
FIGURE 7-1. Histopathology demonstrating A. Gross appearance of the liver. B . Masson trichrome stain, 100×. C. Rhodanine stain, 400×. (Photos courtesy of Dr. Bruce Pawel.)
INCIDENCE AND PATHOPHYSIOLOGY OF WILSON DISEASE
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, the most common genetic disorder of copper metabolism, is a rare autosomal recessive disorder of copper metabolism. In Wilson disease, copper transport is affected by mutations in the ATP7B gene on chromosome 13. Recognition of more distinct mutations of the Wilson disease gene has increased the estimated incidence to as high as 1 in 30 000. The disease is found worldwide, but has higher rates in 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 balance of copper. 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 the generation of free radicals, lipid peroxidation of membranes and DNA, inhibition of protein synthesis, and altered levels of cellular antioxidants.
CLINICAL PRESENTATION OF WILSON DISEASE
The clinical presentation of Wilson disease is variable, with cases presenting with hepatic, neurologic, and psychiatric manifestations or a combination of these. Hemolysis is seen most often in patients who present with acute liver failure. 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 either through family screening or through the incidental finding of Kayser-Fleischer rings on examination are said to be asymptomatic or presymptomatic. There is even 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 (4:1) 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 impact 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. Coombs negative hemolytic anemia is a common complication of Wilson disease when there is acute liver failure and is thought to be secondary to hepatocellular necrosis with resulting release of copper ions in the circulation.
DIAGNOSTIC APPROACH TO WILSON DISEASE
The serious sequelae of a delayed diagnosis of Wilson disease indicate that the disease should be seriously considered and investigated in any patient between 3 and 55 years of age with any unexplained liver and neurologic disease. This is particularly important in children or adolescents with extrapyramidal or cerebellar motor disorders, atypical psychiatric disease, unexplained, hemolysis, and elevated transaminases either in the presence or absence of a family history of liver or neurologic disease. Additionally, individuals who are asymptomatic but whose family member has a confirmed or suspected case of Wilson disease should be investigated. Because the classic triad of hepatic disease, neurologic involvement, and Kayser-Fleischer rings is usually not present in the pediatric population, a combination of clinical findings, biochemical tests, and sometimes genetic testing is necessary to establish the diagnosis.
The American Association for the Study of Liver Diseases (AASLD) updated practice guidelines on Wilson disease in 2008. The AASLD also has a variety of algorithms to approach the diagnosis of the disease.
The AASLD recommends screening patients older than 3 years who have liver disease of unclear etiology, particularly those with accompanying neurologic manifestations. Screening should particularly focus on patients with autoimmune hepatitis, patients with hemolysis in the setting of acute hepatic failure, and any first-degree relatives of newly diagnosed patients.
Ophthalmology examination. Screening and diagnostic testing must include a slit-lamp examination. Ophthalmic slit-lamp 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 the disease. In the presence of neurologic disease, 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 gene affected in Wilson disease affects this transport system for copper and leads to decreased incorporation of copper into ceruloplasmin and decreased circulating levels of copper. Thus, in Wilson disease serum ceruloplasmin is decreased. Ceruloplasmin levels less than 50 mg/L support the diagnosis, but normal levels do not rule it out. Other diseases such as protein-losing enteropathy, nephrotic syndrome, and even heterozygotes for Wilson disease can have low ceruloplasmin levels. Additionally, it 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 it is helpful in monitoring adherence and response to therapy. Urinary copper excretion is usually very high (> 100 μg/24 h) in symptomatic patients, but even greater than 40 μg/24 h is not normal and should be further worked up.
Liver biopsy. Liver copper concentration of more than 250 μg/g of dry tissue (five times the normal concentration) is diagnostic for the disease.
Brain imaging. MRI of the brain looking specifically for structural abnormalities of the basal ganglia can be performed for patients with neurologic manifestation of Wilson disease.
Genetic testing. Genetic studies, specifically mutation analysis by whole gene sequencing, are best reserved for patients in whom the other diagnostic studies have not established the diagnosis but for whom there is still a strong suspicion. Specific known mutation testing can be used to screen first-degree relatives of patients with Wilson disease.
Immediately after confirmation of the disease, therapy should be initiated 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.
While a low-copper diet does not play a great role in the treatment of the disease, it is important for patients to avoid heavy copper-containing foods like 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 the 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 levels. Side effects are more common with higher doses. Sensitivity reactions which include fever, rash, leukopenia, thrombocytopenia, and lymphadenopathy 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 in 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.
Zinc salts taken three times daily seems to protect hepatocytes by inducing metallothionein in enterocytes which blocks the intestinal absorption of copper. Other experimental chelators (tetrathiomolybdate) are available.
The indications for liver transplantation in patients with liver disease include acute hepatic failure (especially in association with hemolysis), advanced cirrhosis with decompensation, and hepatic insufficiency that progresses in the face of adequate treatment with chelation therapy. Liver transplantation in patients with only neurologic disease remains controversial. Patients receiving transplant display total reversal of the biochemical abnormalities they had previously.
Future directions of treatment include gene therapy, but presently early detection and chelation therapy are still the most important aspects of treatment.
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