Jan Pfeiffenberger

Iron metabolism and the role of HFE gene polymorphisms in Wilson disease

Wilson disease (WD) is a rare inherited disorder of copper metabolism, which can lead to severe liver failure and to a variety of neuropsychiatric symptoms. Previous animal studies and case reports suggest that hepatic iron overload and alterations in iron processing are associated with WD. The aim of this study was the assessment of iron metabolism and of the frequency of the most common HFE gene polymorphisms in WD patients.

Pregnancy in Wilson's disease: Management and outcome

Wilsons disease (WD) is a rare inherited disorder of copper metabolism causing toxic hepatic and neural copper accumulation. Clinical symptoms vary widely, from asymptomatic disease to acute liver failure or chronic liver disease with or without neuropsychiatric symptoms. Continuation of specific medical treatment for WD is recommended during pregnancy, but reports of pregnancy outcomes in WD patients are sparse. In a retrospective, multicenter study, 282 pregnancies in 136 WD patients were reviewed. Age at disease onset, age at conception, and WD‐specific treatments were recorded. Maternal complications during pregnancy, rate of spontaneous abortions, and birth defects were analyzed with respect to medical treatment during pregnancy. Worsening of liver function tests was evident during 16 of 282 (6%) pregnancies and occurred in undiagnosed patients as well as in those under medical treatment. Liver test abnormalities resolved in all cases after delivery. Aggravation of neurological symptoms during pregnancy was rare (1%), but tended to persist after delivery. The overall spontaneous abortion rate in the study cohort was 73 of 282 (26%). Patients with an established diagnosis of WD receiving medical treatment experienced significantly fewer spontaneous abortions than patients with undiagnosed WD (odds ratio, 2.853 [95% confidence interval, 1.634‐4.982]). Birth defects occurred in 7 of 209 (3%) live births. Conclusion: Pregnancy in WD patients on anticopper therapy is safe. The spontaneous abortion rate in treated patients was lower than that in therapy‐naïve patients. Although the teratogenic potential of copper chelators is a concern, the rate of birth defects in our cohort was low. Treatment for WD should be maintained during pregnancy, and patients should be monitored closely for hepatic and neurological symptoms. (Hepatology 2018;67:1261‐1269).

Wilson disease: Health-related quality of life and risk for depression.

BACKGROUND Wilson disease is an autosomal recessive disorder of copper metabolism and requires lifelong medical treatment. Therefore, the analysis of quality of life has gathered more attention. Aims of this study were to examine risk for depression and health-related quality of life in patients suffering from Wilson disease. METHODS Sixty-eight patients were included in this retrospective cross sectional study. The Personal Health Questionnaire-9 Depression Scale was used to assess depression. The Short Form-36 Health Survey questionnaire was used to assess health-related quality of life. RESULTS The Personal Health Questionnaire-9 indicated that 21% (14/68) of patients were at risk for major depressive disorders (scores>10) and 35% (24/68) were at risk for mild depression (scores 5-9). Women had significantly lower life quality scores than men. Primary neurologic disease manifestation was associated with significantly lower total Short Form-36 and subdimension scores compared with primary hepatic or mixed presentation. Overall, patients with Wilson disease experienced higher quality of life than patients with other chronic liver diseases. CONCLUSIONS As patients with Wilson disease have a high risk for depressive disorders, active assessment for depression is mandatory. Patients with primary neurological symptoms are at higher risk for reduction of life quality.

Successful combination of direct antiviral agents in liver-transplanted patients with recurrent hepatitis C virus

AIM To analyze the safety and efficiency of direct-acting antiviral (DAA) regimens in liver-transplanted patients with hepatitis C virus (HCV) reinfection. METHODS Between January 2014 and December 2016, 39 patients with HCV reinfection after liver transplantation were treated at our tertiary referral center with sofosbuvir (SOF)-based regimens, including various combinations with interferon (IFN), daclatasvir (DAC), simeprivir (SIM) and/or ledipasvir (LDV). Thirteen patients were treated with SOF + IFN ± RBV. Ten patients were treated with SOF + DAC ± RBV. Fiveteen patients were treated with fixed-dose combination of SOF + LDV ± RBV. One patient was treated with SOF + SIM + RBV. Three patients with relapse were retreated with SOF + LDV + RBV. The treatment duration was 12-24 wk in all cases. The decision about the HCV treatment was made by specialists at our transplant center, according to current available or recommended medications. RESULTS The majority of patients were IFN-experienced (29/39, 74.4%) and had a history of hepatocellular carcinoma (26/39, 66.7%) before liver transplantation. Sustained virological response at 12 wk (SVR12) was achieved in 10/13 (76.9%) of patients treated with SOF + IFN ± RBV. All patients with relapse were treated with fixed-dose combination of SOF + LDV + RBV. Patients treated with SOF + DAC + RBV or SOF + LDV + RBV achieved 100% SVR12. SVR rates after combination treatment with inhibitors of the HCV nonstructural protein (NS)5A and NS5B for 24 wk were significantly higher, as compared to all other therapy regimens (P = 0.007). Liver function was stable or even improved in the majority of patients during treatment. All antiviral therapies were safe and well-tolerated, without need of discontinuation of treatment or dose adjustment of immunosuppression. No serious adverse events or any harm to the liver graft became overt. No patient experienced acute cellular rejection during the study period. CONCLUSION Our cohort of liver-transplanted patients achieved high rates of SVR12 after a 24-wk course of treatment, especially with combination of NS5A and NS5B inhibitors.

Survival of Hepatocellular Carcinoma Patients Treated with Sorafenib beyond Progression

Background/Aim: Sorafenib leads to improved survival in advanced hepatocellular carcinoma (HCC) patients. Continuation of sorafenib beyond progression has been a possible treatment strategy when further approved therapeutic agents are lacking. Methods: We performed a retrospective analysis of all HCC patients at our institution with documented disease progression under treatment with sorafenib. Overall survival (OS) from start of sorafenib treatment was compared between patients who received sorafenib for > 3 weeks beyond progression (group 1) and those who discontinued sorafenib ≤3 weeks after progression (group 2). Group 1 was further subdivided into those patients who received sorafenib for > 3 months (group 1a) and those who received it for ≤3 months (group 1b). Results: A total of 71 patients were analyzed. Median OS for all patients was 15.4 months. OS in group 1 (15.6 months) and 2 (13.0 months) was similar (p = 0.90). Patients in group 1a showed significantly prolonged median OS (19.7 months) compared to that of patients in group 1b (13.6 months, p = 0.004), and they showed a trend towards prolonged OS compared to group 2 (p = 0.126). For patients with a poor prognosis according to their Child-Pugh stage, performance status, alpha-fetoprotein, and response to prior sorafenib treatment, OS was significantly prolonged in group 1 versus group 2 (12.1 vs. 6.4 months, p = 0.019). Conclusion: In HCC patients, continuing sorafenib beyond progression for > 3 months is associated with improved survival compared to discontinuing sorafenib within 3 months. Furthermore, patients with a poor prognosis who continue sorafenib beyond progression in general show significantly prolonged survival.

Wilson disease: symptomatic liver therapy

Wilson disease leads to symptomatic impairment of liver function or liver cirrhosis. Strict adherence to decoppering agents is essential in these patients. Secondary prevention of additional hepatic damage by avoidance of other toxic substances (e.g., alcohol, drugs) and sufficient calorie intake is recommended. Routine examinations in cirrhotic patients include screening for signs of portal hypertension (esophagus varices), development of ascites, and hepatic encephalopathy. Where varices are present, primary or secondary preventive interventions may include treatment with nonselective beta-blockers or variceal ligation, similar to the approach in patients with liver cirrhosis due to other etiologies. For patients presenting with ascites, diuretics are the treatment of choice. Spontaneous bacterial peritonitis can be diagnosed by paracentesis and should be treated with antibiotics. Liver cirrhosis can also lead to accumulation of neurotoxins causing hepatic encephalopathy. It is characterized by unspecific neuropsychiatric impairment and is treated with laxatives and nonresorbable antibiotics. The best prophylaxis is regular defecation. Patients with liver cirrhosis are susceptible for bacterial infections of any cause and sepsis is one of the leading causes of death in these patients. In advanced stages of cirrhosis renal function impairment is a common feature. The hepatorenal syndrome shows a high mortality. Where Wilson disease patients have decompensated liver cirrhosis, liver transplantation should be evaluated.

Factors modifying phenotypic presentation in Wilson disease: authors' reply

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