Medical treatment regimens for WD include copper chelators and zinc salts. Chelating agents are generally first line therapy for symptomatic patients because of their higher decoppering potential compared to zinc salts that indirectly reduce copper by blocking intestinal absorption. D-penicillamine, the first oral copper chelating agent [3], is commonly used worldwide. However intolerance and serious side effects such as immune complex nephritis, nephrotic syndrome, systemic lupus erythematosus and bone marrow suppression led to the use of trientine. [2]. Trientine is an effective initial treatment and maintentance therapy for WD [4]. Due to its better safety profile, trientine was included as an option for first line and maintenance therapy for WD in American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of Liver Diseases (EASL) guidelines [5, 6]. Rare side effects reported for trientine include iron deficiency, systemic lupus erythematosus, dystonia, muscular spasm and myasthenia gravis [7]. Only 6–18 % of orally administered trientine is systemically absorbed [8].
Effects of trientine on the colon were first noted by Dahlman et al. in 1995, profiling two WD patients that experienced colitis while on trientine [9]. Their first patient had experienced side effects with penicillamine, developing uveitis, proteinuria and ANA positivity, and was changed to trientine. Endoscopic evidence of duodenitis and colitis was seen four months after exposure to trientine. Although trientine was initially withdrawn it was later restarted along with steroid. The steroid was eventually withdrawn, and the patient remained on trientine without diarrhea or recurrence of colitis.
The second WD patient was cirrhotic and was initially started on trientine. Diarrhea developed that ceased with the withdrawal of a neuroleptic drug, and trientine was continued. Months later, when symptoms started with a gastroenteritis seen in the whole family, the patient developed bloody diarrhea and had colonoscopic evidence of colitis. After withdrawal of trientine, colitis recurred when penicillamine was administered, suggesting an underlying inflammatory bowel disease.
In our WD patient, trientine was chosen as initial treatment. Colitis developed within a month of exposure to the drug, earlier than in the cases reported above. Her symptoms improved immediately upon withdrawal of trientine, and colitis recurred with rechallenge to this medication. The colitis was visible on colonoscopy from the rectum to the transverse colon. Histologic features included cryptitis, crypt abscesses and multiple foci of fresh and healing ulcerations. The histologic changes are not specific, and could be seen in infectious colitis and evolving inflammatory bowel disease. The lack of well-developed features of chronicity like established crypt architectural distortion and paneth and the timing of the colitis were most helpful in making a diagnosis of trientine colitis, with features similar to those reported in previous cases [9]. The pathophysiological mechanism for the development of colitis is unknown. As noted, there is poor intestinal absorption of trientine from the gut, and the trigger for developing colitis may be a local reaction with the colonic epithelium rather than of autoimmune origin, especially since the reaction was limited to the time of medication exposure.
Treatment with a chelating agent was warranted in our patient with symptomatic disease with neuropsychiatric features dominating the clinical presentation. Due to the continued severe neuropsychiatric symptoms, the re-challenge with trientine was justified. It is worth notion that the steroids required for treatment of trientine induced colitis complicated the differential diagnosis of her psychosis. However, the duration of psychosis (months after steroids were discontinued) and the lack of exacerbation with another challenge of prednisone led to the working diagnosis of psychosis secondary to WD rather than steroid induced psychosis. After the withdrawal of trientine, the patient was effectively treated with zinc therapy. Zinc salts induce intestinal epithelium to produce cytosolic metallothioneins that effectively sequester copper and block new copper absorption. While zinc is indicated for maintenance therapy for WD or initial treatment of asymptomatic WD patients, zinc was used for first line treatment of some patients with neurological WD [10]. Though treatment with zinc can sometimes cause gastric side effects [11] and the achievement of a negative copper balance is slower with zinc, in patients such as ours, zinc therapy was effective over time. Since our patient had psychiatric symptoms, she was treated for these independent of the WD, and was able to withdraw psychiatric therapy over 1–2 years time.
At the time of the reporting of the prior cases of trientine colitis, zinc therapy was a less well accepted alternative treatment of WD. Therefore the re-trial of the drug and attempts at steroid desensitization were warranted. Given the numerous reports demonstrating the efficacy of zinc therapy for WD, there would no longer be justification for desensitization to trientine or d-penicillamine in intolerant patients.
