*Departments of Pediatric Intensive Care, Turkey
‡Pediatric Gastroenterology and Hepatology, Erciyes University Medical Faculty, Kayseri, Turkey.
Received 2 July, 2010
Accepted 25 November, 2010
Address correspondence and reprint requests to Basak Nur Akyıldız, MD, e-mail: firstname.lastname@example.org.
The authors report no conflicts of interest.
Wilson disease (WD) is an autosomal recessive disorder characterized by the accumulation of copper in the body, especially in the liver, brain, kidney, and cornea (1,2). Liver involvement can manifest itself as cirrhosis, chronic active hepatitis, or fulminant hepatic failure (2). Mortality is particularly high in patients in whom fulminant hepatic failure is accompanied by hemolytic crisis (3). Hepatic transplantation is the only treatment for these individuals when copper-chelating agents are insufficient (3,4). Chelating agents such as D-penicillamine and trientine are the primary medications used for treatment (3). Moreover, methods such as plasma exchange (PE) can be lifesaving in the early periods of fulminant hepatic failure when copper should be immediately eliminated from the circulation (3,5).
PE is a procedure that involves the removal of patient's plasma from the blood, substituting a plasma-replacement solution of fresh frozen plasma (FFP) and returning “treated” plasma to the blood circulation. By this procedure, unwanted plasma components are removed and the remaining plasma is returned to the body (6). This procedure can be performed on patients with WD and copper can be removed quickly from the blood. In this way, hemolysis that is caused by the oxidative effects of copper can be eliminated and hepatic functions can be stabilized (4,7,8). PE is effective in treating hepatic encephalopathy and clinical homeostasis in fulminant hepatic failure; it can also eliminate the need for urgent liver transplantation in some cases (5,7–9).
We present data on a 9-year-old girl who presented with hemolytic crisis and jaundice. She was diagnosed with fulminant WD in the early phases and avoided having a liver transplant after the successful implementation of PE in our intensive care unit.
A 9-year-old girl with no history of liver disease presented with jaundice, vomiting, diarrhea, headache, and abdominal pain. Initially, the patient was thought to have hepatitis A, and she was sent home after the examination. Thereafter, she was diagnosed as having hepatic coma and was hospitalized in the intensive care unit because of blurred consciousness and increase in weakness and jaundice.
In the first examination, her overall medical condition was moderate, the skin was icteric, the liver and spleen were balloted by 3 and 2 cm, respectively, and widespread abdominal ascites were apparent. The Glasgow Coma Score (GCS) was 11. Laboratory examinations revealed the following: hemoglobin (Hb) 4.6 g/dL; hematocrit (Hct) 13.6%; white blood cell count (WBC) 17.2 × 103/μL; platelet count (Plt) 112 × 103/μL; total bilirubin/direct bilirubin 32.6/19.5 g/dL; reticulocyte count 15%; direct Coombs test negative; symptoms of hemolysis in the peripheral blood smear; blood urea nitrogen (BUN)/creatinine (Cr) 51.3/2.2 mg/dL; aspartate aminotransferase 178 U/L; alanine aminotransferase 29 U/L; alkaline phosphatase (ALP) 10 U/L; γ-glutamyl transferase 184 U/L; lactate dehydrogenase 1128 U/L; total protein 39 g/L; albumin 28 g/L; prothrombin time 34 seconds; activated partial thromboplastin time (aPTT) 63 seconds; and international normalized ratio 3.06. The blood ammonia level was 63 μmol/L. Restricted fluid intake, lactulose, enema with gentamicin, intravenous antibiotics, and ranitidine were started as treatment for hepatic coma. Erythrocyte suspension (ES), vitamin K, and FFP were given to the patient who was bleeding from the nasogastric tube. Fulminant hepatitis caused by WD was considered because of the laboratory and clinical symptoms; her 24-hour urine serum copper and ceruloplasmin levels were obtained. The 24-hour urine copper level was 1020 μg/g (normal 3–35 μg/g), serum total copper level was 214 μg/g (normal 70–160), and the ceruloplasmin level was 230 g/L (normal 220–580 g/L). Kayser-Fleischer rings were not observed during the eye examination. The WD score was 16. Due to the unavailability of rapid liver transplantation, PE was started to decrease the excessive copper load and prevent hemolytic anemia; therapy with D-penicillamine and zinc was started. During each exchange, 1200 mL of plasma was replaced by the same volume of FFP. Each session lasted between 3 and 4 hours. The amount of copper eliminated per session ranged from 1050 to 6800 μg. No adverse reactions were observed for 4 days of PE. D-Penicillamine and zinc could only be given effectively after the second PE because of vomiting and gastrointestinal system bleeding. Three days after 500 mg/g D-penicillamine was started, the 24-hour urine copper level was 2600 μg/g (>1600 μg/g) (D-penicillamine chelation test).
Although the patient showed clinical improvement with the disappearance of encephalopathy, decreased jaundice, and controlled hemolysis, she was sent to a related center for hepatic transplantation after the 5 PEs because her condition was classified as class C (score 10), according to the Child-Pugh classification, and the factor V level was 10% on the 10th day of hospitalization. After evaluation, urgent transplantation was not considered for the patient, and she was followed up with D-penicillamine, trientine, and zinc treatment. The patient's Child-Pugh score was 7 (class B) at the end of the first month. The laboratory results during hospitalization and follow-up, Hb and serum bilirubin levels, and serum and urine copper levels are shown, respectively, in Table 1, Figure 1, and Figure 2.
Equation (Uncited)Image Tools
After viral hepatitis, WD and metabolic diseases are among the most common reasons for the development of fulminant hepatic failure in Turkey (10). Quantitatively determined serum and 24-hour urine copper levels, decreased serum ceruloplasmin levels, and Kayser-Fleischer rings in the eye are helpful in the diagnosis of fulminant hepatic failure, although they are not the criteria for definitive diagnosis (11). Because of the difficulty in reaching the diagnosis of WD, a number of other laboratory parameters have been developed (12). The urinary copper excretion after penicillamine challenge may be a reliable parameter for suspicious cases (13). A ratio <2 between ALP and bilirubin and serum aminotransferase activity usually <10 times normal are important laboratory parameters to differentiate from other causes of acute liver failure (14,15). Although the best diagnostic test is the quantification of copper in liver biopsy material, it is difficult to use clinically because liver biopsy is not appropriate for most cases because of coagulopathy (16). Our patient, who did not have any history of liver disease, presented with severe anemia, and acute liver and kidney failure. Because WD was suspected, serum urine copper and ceruloplasmin levels were checked after nonimmune hemolytic anemia, and a low level of ALP was detected in the laboratory examinations. Copper levels were high, and the ceruloplasmin level was within the normal range. In addition, the fact that the 24-hour urine copper level was 2600 μg/24 hours (>1600 μg/24 hours) 3 days after the start of 500-mg D-penicillamine treatment supported the diagnosis.
The most important factors that determine the prognosis in hepatic failure related to fulminant WD are the early diagnosis and proper intensive care support (17). In such cases, kidney failure can arise because of severe hemolysis. Mortality is higher especially in patients with severe hemolysis (3). Although the chelator agents such as D-penicillamine are the primary medications for patients with WD, implementation can be difficult because of the secondary complications caused by the underlying liver pathology, such as vomiting and gastrointestinal bleeding. Moreover, the full effects of chelator agents can be seen only 1 to 3 months after the treatment is started (4,18,19). PE was performed on our patient in addition to chelator treatment on the second day of hospitalization, and D-penicillamine could be given regularly after the fourth day because of vomiting and upper gastrointestinal system bleeding. To our knowledge, PE when initiated early in the phase of hemolytic anemia and fulminant hepatitis reduces circulatory copper, bilirubin, and further hemolysis. In our case, the amount of copper eliminated per session ranged from 1050 to 6800 μg and marked total and unconjugated bilirubin reduction was detected after the first PE. The hemolysis was well controlled, and only 1 U of ES was given after the last PE.
Therefore, methods such as PE, plasmapheresis, continuous venovenous hemodialysis, and molecular adsorbent recycling system become issues when more and quicker removal of copper from the circulation is important in acute conditions (3,5). These methods can facilitate liver transplantation and, in some cases, even eliminate the need for urgent transplantation by ameliorating hepatic dysfunctions such as hepatic coma and coagulopathy and eliminating hemolysis caused by the oxidative effects of copper (7). No systematic study in the literature compares all of the methods for their effectiveness in removing copper from the circulation. Although an average of 20.6 mg of copper can be removed from the circulation by plasmapheresis, 3.4 mg of copper can be removed by hemodiafiltration (11). More effective replacement of coagulation factors via PE is also considerably useful to control bleeding caused by coagulopathy. Liver transplantation was not required for 3 of 10 patients who were treated with plasmapheresis in the early period (4,7). The extracorporeal dialysis system called molecular adsorbent recycling system is a newer application compared with PE. It is an expensive method in Turkey and more experience using this modality is necessary. Six cases were reported in the literature and all of them had liver transplantation later (3,20). She is the youngest patient presenting with fulminant WD, including renal failure, hepatic failure, encephalopathy, and severe hemolysis in the literature. Despite renal failure we detected improvement of renal functions day by day via only PE and did not need continuous venovenous hemodialysis in this patient.
In conclusion, PE allows transplantation with the patients who are in better condition. In some patients with acute fulminant WD, PE can eliminate the necessity of transplantation with early diagnosis and successful treatment.
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