The diagnosis of PBC is generally based on the following criteria (
4): biochemical evidence of cholestasis with elevated serum alkaline phosphatase, presence of AMA and histopathologic evidence of nonsuppurative cholangitis and destruction of small or medium-sized bile ducts if a biopsy is performed. The patient in this study accorded with the characters mentioned above, with elevation of ALKP, positive AMA and typical pathological features, should be definitely diagnose with PBC.
However, the patient’s liver histology showed diffusely deposition of copper throughout the hepatic lobule, which was more than most of PBC patients. In generally, copper retention is a phenomenon secondary to PBC, the metal being confined to the periportal region of the liver lobules. At the time of diagnosis, 55% of patients with PBC have liver copper concentrations below the range occurring in WD. So, WD must be considered in the differential diagnosis.
Typically, the combination of Kayser-Fleischer (K-F) rings and a low serum ceruloplasmin (< 0.1 g/L) level is sufficient to establish a diagnosis of WD (
5). However, WD could not be ruled out in this patient though there was no K-F rings and with normal ceruloplasmin. Other assay for diagnosing WD such as measurement of serum ceruloplasmin oxidase activity, which was superior to immunologic assays, was generally not available in routine labs ( 6). Thus, the combination of tests reflecting disturbed copper metabolism may be needed for many patients. Additionally, for diagnostic purposes, a liver biopsy is required if the clinical signs and noninvasive tests do not allow a final diagnosis of WD or if there is suspicion of other or additional liver pathologies. Think back of this patient’s first liver biopsy, it indeed showed several features suggesting the early histologic abnormalities of WD, including mild steatosis (both microvesicular and macrovesicular), glycogenated nuclei in hepatocytes, and focal hepatocellular necrosis. However, with progressive parenchymal damage, biliary fibrosis even subsequently cirrhosis and diffusely copper deposition were showed in the liver.
Furthermore, We got the powerful evidence of WD in this patient by using the Wilson’s disease scoring system, which was based on all available tests and proposed by the Working Party at the 8th International Meeting on Wilson’s disease (
Table 1) ( 7). A score of greater than or equal to four establishes a diagnosis of WD. The score of this patient is 7, clearly indicating a diagnosis of WD.
Table 1. Scoring System Developed at the Eighth International Meeting on Wilson’s Disease, Leipzig, 2001
Clinical Tests and Evaluations Score Typical Clinical Symptoms and Signs Kayer-Flesicher rings Present 2 Absent a 0 Neurologic symptom b Severe 2 Mild 1 Absent a 0 Serum ceruloplasmin, g/L Normal, > 0.2 a 0 0.1 - 0.2 1 < 0.1 2 Coombs-negative hemolytic anemia mutation analysis Present 1 Absent a 0 Other Tests Liver copper (in absence of cholestasis), μmol/g > 5 × ULN, (> 4) 2 0.8 - 4 1 Normal, (< 0.8) -1 Rhodamine-positive hepatocyte on biopsy a 1 Urinary copper (in absence of acute hepatitis) Normal 0 1 - 2 × ULN 1 > 2 × ULN a 2 Normal, but > 5 × ULN after D-penicillamine 2 Mutation analysis Two chromosome mutations a 4 One chromosome mutation 1 No mutations detected 0 Evaluation c Diagnosis highly likely ≥ 4 Diagnosis probable, more tests needed 3 Diagnosis very unlikely ≤ 2
aDiagnostic scoring of Wilson’s disease in this case; ULN, upper limit of normal range.
bTypical abnormalities at brain MRI.
cEvaluations based on total scores.
It should be noted that copper deposition in the liver is not the specific feature of WD or PBC. There were different mechanisms for them. Wilson’s disease is an inborn error of copper metabolism, whereas in PBC, cholestasis and biliary cirrhosis dominate the clinical and biochemical evolution of the disease, with liver copper retention occurring as a complication of cholestasis. Also, several non-Wilson’s diseases of copper overload have been described, idiopathic copper toxicosis (ICT), primary sclerosing cholangitis, and endemic Tyrolean infantile cirrhosis (ETIC), which share the common end point of cirrhosis due to excessive copper accumulation. Therefore, when there is copper deposition in the liver, many diseases have to be identified.
In conclusion, co-occurrence of PBC with WD is rare. Patients with WD who concurrently have other liver diseases, particularly PBC, hepatitis C viral infection, hemochromatosis, hemochromatosis heterozygote, or primary sclerosing cholangitis may present with more severe hepatic injury and show greater mortality (
8). Often the WD diagnosis is delayed in these individuals as other disease entities are considered first. Early liver biopsy and genetic mutation analysis are necessary and helpful for the final diagnosis. Fortunately, treatment with UDCA, zinc and sodium dimercaptopropane sulfonate is effective for this patient.