Hepatocellular carcinoma risk in sub-Saharan African and Afro-Surinamese individuals with chronic hepatitis B living in Europe.

BACKGROUND & AIMS: Sub-Saharan African (SSA) ethnicity has been associated with a higher risk of hepatocellular carcinoma (HCC) among individuals with chronic hepatitis B in cross-sectional studies. However, the incidence of HCC and performance of HCC risk scores in this population are unknown. METHODS: We conducted an international multicenter retrospective cohort study of all consecutive HBV-monoinfected individuals of SSA or Afro-Surinamese (AS) ethnicity managed at sites in the Netherlands, the United Kingdom and Spain. We assessed the 5- and 10-year cumulative incidences of HCC in the overall study population, among different clinically relevant subgroups and across (m)PAGE-B subgroups. Next, we explored the different risk factors for HCC. RESULTS: During a median follow-up of 8 years, we analyzed 1,473 individuals of whom 34 developed HCC. The 5- and 10-year cumulative incidences of HCC were 1% and 2.4%. The 10-year cumulative incidence of HCC was 0.7% among individuals without advanced fibrosis at baseline, compared to 12.1% among individuals with advanced fibrosis (p <0.001). Higher age (adjusted hazard ratio [aHR] 1.05), lower platelet count (aHR 0.98), lower albumin level (aHR 0.90) and higher HBV DNA log10 (aHR 1.21) were significantly associated with HCC development. The 10-year cumulative incidence of HCC was 0.5% among individuals with a low PAGE-B score, compared to 2.9% in the intermediate- and 15.9% in the high-risk groups (p <0.001). CONCLUSIONS: In this unique international multicenter cohort of SSA and AS individuals with chronic hepatitis B, we observed 5- and 10-year cumulative HCC risks of 1% and 2.4%, respectively. The risk of HCC was negligible for individuals without advanced fibrosis at baseline, and among individuals with low baseline (m)PAGE-B scores. These findings can be used to guide HCC surveillance strategies. IMPACT AND IMPLICATIONS: Sub-Saharan African ethnicity has been associated with a higher risk of hepatocellular carcinoma among individuals with chronic hepatitis B. In this international multicenter cohort study of sub-Saharan African and Afro-Surinamese individuals living with chronic hepatitis B in Europe, we observed 5- and 10-year cumulative incidences of hepatocellular carcinoma of 1% and 2.4%, respectively. The risk was negligible among individuals without advanced fibrosis and a low baseline (m)PAGE-B score. These findings can be used to guide HCC surveillance strategies in this population.

Association Between the Presence of Metabolic Comorbidities and Liver-Related Events in Patients With Chronic Hepatitis B.

BACKGROUND & AIMS: Patients with chronic hepatitis B (CHB) are at increased risk of hepatocellular carcinoma and (liver-related) mortality. In addition to hepatitis B-related factors, metabolic comorbidities may contribute to the progression of fibrosis. Therefore, we studied the association between metabolic comorbidities and adverse clinical outcomes in patients with CHB. METHODS: We conducted a retrospective cohort study of CHB patients attending the Erasmus MC University Medical Center (Rotterdam, The Netherlands) and CHB patients who underwent liver biopsy at the Toronto General Hospital (Toronto, Canada). The presence of metabolic comorbidities (ie, overweight, diabetes mellitus, hypertension, and dyslipidemia) was assessed based on chart review. The primary end point was liver-related events, defined as the first composite of hepatocellular carcinoma, liver transplantation, or liver-related mortality. RESULTS: We analyzed 1850 patients, of whom 926 (50.1%) were overweight, 161 (8.7%) had hypertension, 116 (6.3%) had dyslipidemia, and 82 (4.4%) had diabetes. During a median follow-up period of 7.3 years (interquartile range, 2.9-11.5 y), a total of 111 first events were recorded. Hypertension (hazard ratio [HR], 8.3; 95% CI, 5.5-12.7), diabetes (HR, 5.4; 95% CI, 3.2-9.1), dyslipidemia (HR, 2.8; 95% CI, 1.6-4.8), and overweight (HR, 1.7; 95% CI, 1.1-2.5) were associated with an increased risk for liver-related events. The presence of multiple comorbidities further increased the risk. Findings were consistent for patients with and without cirrhosis, among noncirrhotic hepatitis B e antigen-negative patients with hepatitis B virus DNA less than 2000 IU/mL and in multivariable analysis adjusting for age, sex, ethnicity, hepatitis B e antigen status, hepatitis B virus DNA, use of antiviral therapy, and the presence of cirrhosis. CONCLUSIONS: Metabolic comorbidities in CHB patients are associated with an increased risk for liver-related events, with the highest risk observed in patients with multiple comorbidities. Findings were consistent in various clinically relevant subgroups, underscoring the need for thorough metabolic assessment in patients with CHB.

Effects of on-treatment ALT flares on serum HBsAg and HBV RNA in patients with chronic HBV infection.

As pegylated interferon alpha (PEG-IFN-α) is increasingly used in combination regimens of novel drugs, we aimed to characterize ALT flares and their relationship with serum HBsAg and HBV RNA kinetics in a large combined cohort of chronic hepatitis B (CHB) patients on PEG-IFN-α-based therapy. In this post hoc analysis of four international randomized trials, 269/130/124/128 patients on PEG-IFN-α monotherapy, PEG-IFN-α plus nucleos(t)ide analogue (NA) de novo combination, PEG-IFN-α add-on to NA or NA monotherapy were included, respectively. A flare was defined as an episode of ALT ≥5 × ULN. The association between flares and HBsAg and HBV RNA changes were examined. On-treatment flares occurred in 83/651 (13%) patients (median timing/magnitude: week 8 [IQR 4-12], 7.6 × ULN [IQR 6.2-10.5]). Flare patients were more often Caucasians with genotype A/D and had higher baseline ALT, HBV DNA, HBV RNA and HBsAg levels than the no-flare group. More flares were observed on PEG-IFN-α monotherapy (18%) and PEG-IFN+NA de novo combination (24%) vs. PEG-IFN-α add-on (2%) or NA monotherapy (1%) (p < .001). On-treatment flares were significantly and independently associated with HBsAg and HBV RNA decline ≥1 log10 at the final visit declines started shortly before the flare, progressing towards 24 weeks thereafter. On-treatment flares were seen in 16/22 (73%) patients who achieved HBsAg loss. In conclusion, ALT flares during PEG-IFN-α treatment are associated with subsequent HBsAg and HBV RNA decline and predict subsequent HBsAg loss. Flares rarely occurred during PEG-IFN-α add-on therapy and associated with low HBsAg loss rates. Combination regimens targeting the window of heightened response could be promising.

The impact of PNPLA3 (rs738409 C>G) polymorphisms on liver histology and long-term clinical outcome in chronic hepatitis B patients.

BACKGROUND & AIMS: We aimed to assess the association between the patatin-like phospholipase domain-containing-3 (PNPLA3) I148M polymorphism, liver histology and long-term outcome in chronic hepatitis B (CHB) patients. METHODS: We enrolled 531 consecutive treatment naïve CHB patients diagnosed from 1985 to 2012 with an available liver biopsy for reassessment, and sample for genetic testing. Data on all-cause mortality and hepatocellular carcinoma (HCC) at long-term follow-up were obtained from national database registries. RESULTS: The prevalence of steatohepatitis increased with PNPLA3 CC (14%), CG (20%) and GG (43%) (P < 0.001). The association was altered by both gender (P = 0.010) and overweight (P = 0.015): the effect of PNPLA3 on steatohepatitis was most pronounced among non-overweight females (adjusted OR 13.4, 95%CI: 3.7-51.6, P < 0.001), and non-overweight males (adjusted OR 2.4, 95%CI: 1.4-4.3, P = 0.002). Furthermore, PNPLA3 GG genotype was associated with iron depositions (OR 2.8, 95%CI: 1.2-6.4, P = 0.014) and lobular inflammation (OR 2.2, 95%CI: 1.1-4.5, P = 0.032), but not with advanced fibrosis (OR 1.1, 95%CI: 0.7-1.8, P = 0.566). The median follow-up was 10.1 years (interquartile range 5.6 - 15.8), during which 13 patients developed HCC and 28 died. Steatohepatitis was associated with all-cause mortality [Hazard ratio (HR) 3.1, 95%CI: 1.3-7.3, P = 0.006] and HCC (HR 2.8, 95%CI: 0.9-9.2, P = 0.078), but no significant association was observed for PNPLA3. CONCLUSIONS: In this cohort of biopsied CHB patients, PNPLA3 was independently associated with steatosis, steatohepatitis, lobular inflammation and iron depositions, but not with advanced fibrosis, HCC development or all-cause mortality. The effect of PNPLA3 on steatohepatitis was particularly pronounced among female patients without severe overweight.

Sarcopenia impairs survival in patients with potentially curable hepatocellular carcinoma.

BACKGROUND: A reduction in skeletal muscle mass (sarcopenia) independently predicts poor survival in patients with hepatocellular carcinoma (HCC) undergoing treatment with curative intent. Whether this is due to an increased risk of recurrence and disease specific death, or due to an increased risk of postoperative morbidity and mortality is currently unclear. In this study, we investigate the association between sarcopenia and death in a cohort of HCC patients undergoing treatment with curative intent. METHODS: Patients undergoing surgical resection or radiofrequency ablation for lesions ≤ 3 cm between 2002 and 2013 were identified. Clinicopathological characteristics, CT-assessed sarcopenia and outcomes were analyzed. RESULTS: Among 90 patients, 52 (57.8%) were found to be sarcopenic. Sarcopenic patients had a limited overall survival (median: 33 months vs. non-sarcopenic median: 105 months; P = 0.002), but not disease-free survival. Sarcopenia was an independent predictor for overall survival in multivariate Cox-regression analysis (HR 3.756; P = 0.001). Major complications (32.7% vs. 13.2%, P = 0.033) and treatment-related mortality (17.3% vs. 2.6%, P = 0.029) were more frequent in sarcopenic patients. CONCLUSION: Sarcopenia impairs survival in patients with potentially curable hepatocellular carcinoma, mainly due to an increase in treatment-related mortality.

Problems and needs in patients with incurable esophageal and pancreaticobiliary cancer: a descriptive study.

Patients with incurable esophageal cancer (EC) or pancreaticobiliary cancer (PBC) often have multiple symptoms and their quality of life is poor. We investigated which problems these patients experience and how often care is expected for these problems to provide optimal professional care. Fifty-seven patients with incurable EC (N = 24) or PBC (N = 33) from our outpatient clinic completed the validated "Problems and Needs for Palliative Care" (PNPC) questionnaire and two disease-specific quality of life questionnaires, European Organization for Research and Treatment in Cancer (EORTC). Although patients in general had several problems, physical, emotional, and loss of autonomy (LOA) problems were most common. For these physical and emotional problems, patients also expected professional care, although to a lesser extent for LOA problems. Inadequate care was received for fatigue, fear, frustration, and uncertainty. We conclude that an individualized approach based on problems related to physical, emotional, and LOA issues and anticipated problems with healthcare providers has priority in the follow-up policy of patients with incurable upper gastrointestinal cancer. Caregivers should be alert to discuss needs for fatigue, feelings of fear, frustration, and uncertainty.

MRI features of inflammatory hepatocellular adenomas on hepatocyte phase imaging with liver-specific contrast agents.

PURPOSE: To evaluate the presentation of inflammatory hepatocellular adenomas (HCAs) on hepatocyte phase MRI. MATERIALS AND METHODS: We retrospectively reviewed the MRI features of histologically proven HCAs on hepatocyte phase imaging. Twenty-one lesions (17 with inflammatory subtype) were scanned with gadobenate dimeglumine. Signal intensities of the lesions were assessed in the hepatocyte phase and on the T1-weighted sequences before contrast. RESULTS: After gadobenate dimeglumine injection, 71% (12/17) of the inflammatory HCAs showed areas of iso- or hyperintensity to the surrounding liver in the hepatocyte phase. In 82% (10/12) of the iso- or hyperintense lesions, this was found over more than 75% of the lesion surface. None of the noninflammatory HCAs showed areas of iso- or hyperintensity to the surrounding liver in the hepatocyte phase. From these 12, 7 were hyperintense on T1-weighting before contrast due to liver steatosis, 2 due to intrinsic hyperintensity (on the in-phase sequence), and 3 were isointense. CONCLUSION: In contrast to noninflammatory HCAs, inflammatory HCAs can show areas of iso- to hyperintensity to the surrounding liver in the hepatocyte phase; therefore, other typical imaging features should also be used to distinguish between HCAs and FNHs.

Automated Assessment of T2-Weighted MRI to Differentiate Malignant and Benign Primary Solid Liver Lesions in Noncirrhotic Livers Using Radiomics.

RATIONALE AND OBJECTIVES: Distinguishing malignant from benign liver lesions based on magnetic resonance imaging (MRI) is an important but often challenging task, especially in noncirrhotic livers. We developed and externally validated a radiomics model to quantitatively assess T2-weighted MRI to distinguish the most common malignant and benign primary solid liver lesions in noncirrhotic livers. MATERIALS AND METHODS: Data sets were retrospectively collected from three tertiary referral centers (A, B, and C) between 2002 and 2018. Patients with malignant (hepatocellular carcinoma and intrahepatic cholangiocarcinoma) and benign (hepatocellular adenoma and focal nodular hyperplasia) lesions were included. A radiomics model based on T2-weighted MRI was developed in data set A using a combination of machine learning approaches. The model was internally evaluated on data set A through cross-validation, externally validated on data sets B and C, and compared to visual scoring of two experienced abdominal radiologists on data set C. RESULTS: The overall data set included 486 patients (A: 187, B: 98, and C: 201). The radiomics model had a mean area under the curve (AUC) of 0.78 upon internal validation on data set A and a similar AUC in external validation (B: 0.74 and C: 0.76). In data set C, the two radiologists showed moderate agreement (Cohen's κ: 0.61) and achieved AUCs of 0.86 and 0.82. CONCLUSION: Our T2-weighted MRI radiomics model shows potential for distinguishing malignant from benign primary solid liver lesions. External validation indicated that the model is generalizable despite substantial MRI acquisition protocol differences. Pending further optimization and generalization, this model may aid radiologists in improving the diagnostic workup of patients with liver lesions.

Non-contrast short MRI surveillance for HCC screening: the study protocol of the SMS-HCC prospective multicenter study.

Hepatocellular carcinoma (HCC) comprises 75 to 85% of all primary liver cancers. Current guidelines recommend a biannual HCC surveillance using ultrasound (US) for high-risk patients. However, due to its low sensitivity for detection of early-stage HCC lesions, there is an urgency for more sensitive surveillance tools. Here, we describe the potential of a short MRI surveillance (SMS) protocol for HCC, including axial T1-weighted in-out phase, fat-saturated T2-weighted, and diffusion-weighted sequences. In this prospective, multicenter, patient cohort study, patients will be recruited from existing HCC surveillance cohorts of six medical centers in The Netherlands. Surveillance patients who undergo biannual US, will be invited for SMS on the same day for 3 years. In case of a suspicious finding on either US or SMS, patients will be invited for a full MRI liver protocol including gadolinium-based contrast agent intravenous injection within 2 weeks. To our knowledge, this will be the first study to perform a head-to-head comparison with a paired US-MRI design. We hypothesize that the sensitivity of SMS for detection of early-stage HCC will be higher than that of US leading to improved survival of surveillance patients through timely HCC diagnosis. Furthermore, we hypothesize that the SMS-HCC protocol will prove cost-effective.Relevance statement The US sensitivity for detecting early-stage HCC has been reported to be less than 50%. We expect that the proposed SMS will detect at least twice as many early-stage HCC lesions and therefore prove to be cost-effective. Key points • The low sensitivity of US necessitates better imaging tools for HCC screening.• This is the first study with a paired US-MRI design.• This design will allow a head-to-head comparison in both diagnostics and patient-acceptance.• We expect that SMS can contribute to a higher survival rate.

Relapse is almost universal after withdrawal of immunosuppressive medication in patients with autoimmune hepatitis in remission.

BACKGROUND & AIMS: Current treatment strategies in autoimmune hepatitis (AIH) include long-term treatment with corticosteroids and/or azathioprine. Here we determined the risk of relapse after drug withdrawal in patients in long-term remission and factors associated with such a relapse. METHODS: A total of 131 patients (out of a cohort including 844 patients) from 7 academic and 14 regional centres in the Netherlands were identified in whom treatment was tapered after at least 2 years of clinical and biochemical remission. Relapse was defined as alanine-aminotransferase levels (ALT) three times above the upper limit of normal and loss of remission as a rising ALT necessitating the reinstitution of drug treatment. RESULTS: During follow-up, 61 (47%) patients relapsed and 56 (42%) had a loss of remission. In these 117 patients, 60 patients had fully discontinued medication whereas 57 patients were still on a withdrawal scheme. One year after drug withdrawal, 59% of the patients required retreatment, increasing to 73% and 81% after 2 and 3 years, respectively. Previous combination therapy of corticosteroids and azathioprine, a concomitant autoimmune disease and younger age at time of drug withdrawal were associated with an increased risk of relapse. Subsequent attempts for discontinuation after initial failure in 32 patients inevitably resulted in a new relapse. CONCLUSIONS: This retrospective analysis indicates that loss of remission or relapse occurs in virtually all patients with AIH in long-term remission when immunosuppressive therapy is discontinued. These findings indicate a reluctant attitude towards discontinuation of immunosuppressive treatment in AIH patients.

Transarterial Chemoembolization With Drug-Eluting Beads Versus Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma: Outcomes From a Multicenter, Randomized, Phase 2 Trial (the TRENDY Trial).

PURPOSE: To compare transarterial chemoembolization delivered with drug eluting beads (TACE-DEB) with stereotactioc body radiation therapy (SBRT) in patients with hepatocellular carcinoma (HCC) in a multicenter randomized trial. METHODS AND MATERIALS: Patients were included if they were eligible for TACE. They could also be recruited if they required treatment prior to liver transplantation. A maximum of four TACE-DEB procedures and ablation after incomplete TACE-DEB were both allowed. SBRT was delivered in six fractions of 8-9Gy. Primary end point was time to progression (TTP). Secondary endpoints were local control (LC), overall survival (OS), response rate (RR), toxicity, and quality of life (QoL). The calculated sample size was 100 patients. RESULTS: Between May 2015 and April 2020, 30 patients were randomized to the study. Due to slow accrual the trial was closed prematurely. Two patients in the SBRT arm were considered ineligible leaving 16 patients in the TACE-DEB arm and 12 in the SBRT arm. Median follow-up was 28.1 months. Median TTP was 12 months for TACEDEB and 19 months for SBRT (p=0.15). Median LC was 12 months for TACE-DEB and >40 months (not reached) for SBRT (p=0.075). Median OS was 36.8 months for TACEDEB and 44.1 months for SBRT (p=0.36). A post-hoc analysis showed 100% for SBRT 1- and 2-year LC, and 54.4% and 43.6% for TACE-DEB (p=0.019). Both treatments resulted in RR>80%. Three episodes of possibly related toxicity grade ≥3 were observed after TACE-DEB. No episodes were observed after SBRT. QoL remained stable after both treatment arms. CONCLUSIONS: In this trial, TTP after TACE-DEB was not significantly improved by SBRT, while SBRT showed higher local antitumoral activity than TACE-DEB, without detrimental effects on OS, toxicity and QoL. To overcome poor accrual in randomized trials that include SBRT, and to generate evidence for including SBRT in treatment guidelines, international cooperation is needed.

Hepatitis E virus infection among solid organ transplant recipients, the Netherlands.

We screened 1,200 living heart, lung, liver, and kidney transplant recipients for hepatitis E virus infection by reverse transcription PCR. In 12 (1%) patients, hepatitis E virus infection was identified; in 11 patients, chronic infection developed. This immunocompromised population is at risk for hepatitis E virus infection.

Competence measurement during colonoscopy training: the use of self-assessment of performance measures.

OBJECTIVES: We evaluated a new assessment technique for colonoscopy training. METHODS: We prospectively evaluated colonoscopy skills during training using the Rotterdam Assessment Form for colonoscopy. The questionnaire covers cecal intubation, procedural time, and subjective grading of performance. Individual learning curves are compared with a group reference. RESULTS: Nineteen trainees self-assessed 2,887 colonoscopies. The cecal intubation rate improved from 65% at baseline to 78% and 85% after 100 and 200 colonoscopies, respectively. In our training program the 90% threshold was reached after 280 colonoscopies on average. Cecal intubation time improved from 13:10 minutes at baseline to 9:30 and 8:30 after 100 and 200 colonoscopies, respectively. CONCLUSIONS: This novel self-assessment form allows individual learning curves to be compared with a group reference, provides data on the development of dexterity skills and individual training targets, and stimulates trainees to identify steps for self-improvement.

B-cell activating factor and IL-21 levels predict treatment response in autoimmune hepatitis.

Background & Aims: Increased serum IgG and autoantibodies suggest involvement of B cells in autoimmune hepatitis (AIH). The aim of this study was to assess levels of B cell activating factor of the tumour necrosis family (BAFF), IL-21, and circulating B cell populations in AIH and correlate these to treatment response. Methods: BAFF and IL-21 levels were determined in 66 patients with AIH before treatment and 10 healthy controls. Flow cytometry was performed on circulating B cells of 10 patients with AIH and 12 healthy controls. Results: Based on BAFF and IL-21 levels, untreated patients with AIH were divided into 3 groups: 27 (41%) patients with normal BAFF and IL-21 (normal BAFF), 27 (41%) patients with elevated BAFF but normal IL-21 (high BAFF), and 12 (18%) patients with elevated IL-21 (high IL-21). The high BAFF group presented with higher bilirubin compared with the normal BAFF and high IL-21 groups (159 vs. 26 vs. 89 µmol/L; p = 0.001; Mann-Whitney U test). After 12 months of treatment, 54% of the high BAFF group reached remission compared with 34% of the normal BAFF group and 0% of the high IL-21 group (p = 0.006, Chi-square test). During follow-up, 3 patients (25%) with high IL-21 developed primary sclerosing cholangitis (PSC) variant syndrome. Autoimmune-associated B cells were increased in patients with AIH compared with healthy controls (4.4 vs. 1.4%; p = 0.003, Mann-Whitney U test). BAFF levels were correlated positively with naïve B cells (p = 0.01) and negatively with class-switched B cells (p = 0.003) and nonclass-switched B cells (p = 0.005, Spearman correlation). Discussion: Using BAFF and IL-21, we identified different immunological phenotypes of AIH with a different presentation, treatment response, and outcome. Patients with high IL-21 had the poorest treatment response and a risk of developing PSC variant syndrome. BAFF level was related to shifts in circulating B-cell populations. Lay summary: In patients with untreated autoimmune hepatitis (AIH), circulating B-cell activating factor of the tumour necrosis family (BAFF), IL-21, and B-cell populations were determined. Three subgroups were identified: with (1) normal BAFF and IL-21, (2) elevated BAFF and normal IL-21, and (3) elevated IL-21. Remission after 1-year treatment occurred in 54, 34, and 0% in Groups 1, 2, and 3, respectively. Group 2 had higher bilirubin, indicating more liver dysfunction. In 25% of patients with high IL-21, AIH-PSC variant syndrome developed, but none in the other groups. Autoimmune-associated B cells were elevated and BAFF levels correlated with certain B cells.

Management of hepatocellular adenoma during pregnancy.

BACKGROUND & AIMS: Hepatocellular adenoma in pregnant women requires special considerations because of the risk of hormone induced growth and rupture. To prevent these potential lethal complications, pregnancy is either often discouraged or the surgical resection of large adenomas is recommended. It may be questioned whether it is justified to deny a young woman a pregnancy, as the biological behaviour of hepatocellular adenoma may be less threatening than presumed. In this study we establish the management of hepatocellular adenoma during pregnancy based on our own experience and literature. METHODS: Twelve women with documented hepatocellular adenoma were closely monitored during a total of 17 pregnancies between 2000 and 2009. Their files were reviewed. RESULTS: In four cases, hepatocellular adenomas grew during pregnancy, requiring a Caesarean section in one patient (two pregnancies) at 36 and 34 weeks because of an assumed high risk of rupture. In one case radiofrequency ablation therapy was applied in the first trimester to treat a hormone sensitive hepatocellular adenoma, thereby excluding potential growth later in pregnancy. No intervention was performed in the other 14 cases and all pregnancies had an uneventful course with a successful maternal and fetal outcome. CONCLUSIONS: A "wait and see" management may be advocated in pregnant women presenting with a hepatocellular adenoma. In women with large tumours or in whom hepatocellular adenoma had complicated previous pregnancies, surgical resection may be recommended. In women with smaller adenomas it may no longer be necessary to discourage pregnancy.

Long-term therapy with tenofovir is effective for patients co-infected with human immunodeficiency virus and hepatitis B virus.

BACKGROUND & AIMS: We investigated the long-term efficacy and renal safety of tenofovir disoproxil fumarate (TDF), administered to patients co-infected with human immunodeficiency virus and hepatitis B virus (HBV) as part of an antiretroviral therapy. METHODS: We performed a multicenter, prospective cohort study of 102 patients co-infected with human immunodeficiency virus and HBV who were treated with TDF. RESULTS: At baseline, 80% of patients had a detectable viral load (HBV DNA >20 IU/mL). Among patients positive for hepatitis B e antigen (HBeAg) (n = 67), 92% had a virologic response (HBV DNA <20 IU/mL) after 5 years of treatment. There was no difference between patients with or without lamivudine resistance at baseline (P = .39). Loss rates of HBeAg and hepatitis B s antigen (HBsAg) were 46% and 12%, respectively. Among HBeAg-negative patients (n = 15), 100% had a virologic response after 4 years of treatment and 2 (13%) lost HBsAg. Twenty subjects (20%, all HBeAg-negative) had undetectable HBV DNA at baseline; during a median follow-up period of 52 months (interquartile range, 41-63 mo), 19 (95%) maintained a virologic response and 2 (10%) lost HBsAg. Overall, one patient acquired a combination of resistance mutations for anti-HBV drugs and experienced a virologic breakthrough. Three (3%) patients discontinued TDF because of increased serum creatinine levels. The estimated decrease in renal function after 5 years of TDF therapy was 9.8 mL/min/1.73 m(2), which was most pronounced shortly after TDF therapy was initiated. CONCLUSIONS: TDF, administered as part of antiretroviral therapy, is a potent anti-HBV agent with a good resistance profile throughout 5 years of therapy. Only small nonprogressive decreases in renal function were observed.

Management of liver adenomatosis by radiofrequency ablation.

Traditionally, surgical resection has been the treatment of choice in many patients with hepatocellular adenoma because of the risk of rupture, hemorrhage and malignant transformation. However, some patients are not amenable for surgery due to the extensive involvement of the liver, as in patients with liver adenomatosis. We report 2 cases with liver adenomatosis in which we combined surgery with open and percutaneous radiofrequency ablation for lesions located in both lobes of the liver. Minimal invasive treatment including radiofrequency ablation may offer new perspectives in the treatment of patients with liver adenomatosis.

A case series of proton pump inhibitor-induced hypomagnesemia.

Proton pump inhibitor (PPI)-induced hypomagnesemia has been recognized since 2006. Our aim was to further characterize the clinical consequences and possible mechanisms of this electrolyte disorder using 4 cases. Two men (aged 63 and 81 years) and 2 women (aged 73 and 62 years) had been using a PPI (esomeprazole, pantoprazole, omeprazole, and rabeprazole, 20-40 mg) for 1-13 years. They developed severe hypomagnesemia (magnesium, 0.30 +/- 0.28 mEq/L; reference, 1.40-2.10 mEq/L) with hypocalcemia (calcium, 6.4 +/- 1.8 mg/dL), relative hypoparathyroidism (parathyroid hormone, 43 +/- 6 pg/mL), and extremely low urinary calcium and magnesium excretion. One patient was admitted with postanoxic encephalopathy after a collapse likely caused by arrhythmia. The others had electrocardiogram abnormalities (prolonged QT interval, ST depression, and U waves). Concomitant hypokalemia (potassium, 2.8 +/- 0.1 mEq/L) was considered the trigger for these arrhythmias. Hypomagnesemia-induced kaliuresis (potassium excretion, 65 +/- 24 mEq/L) was identified as the cause of hypokalemia. This series of PPI-induced hypomagnesemia shows that this is a generic effect. It also indicates that hypomagnesemia may occur within 1 year of PPI therapy initiation and can have serious clinical consequences, likely triggered by the associated hypokalemia. A high index of suspicion is required in PPI users for unexplained hypomagnesemia, hypocalcemia, hypokalemia, or associated symptoms.

Colorectal cancer in post-liver transplant recipients.

PURPOSE: Several malignancies have been reported to occur more often after liver transplantation. Whether this is also true for colorectal carcinoma is controversial. Our aims were 1) to compare the observed rate of colorectal carcinoma in a post-liver transplantation cohort with incidence data from the general Dutch population, and 2) to stratify for patients with and without primary sclerosing cholangitis, because primary sclerosing cholangitis is well established as a risk factor for colorectal carcinoma. METHODS: We searched the medical records of liver transplantation patients who had a liver transplantation in our center between 1986 and 2007 with a follow-up of at least 3 months. Incidence data from the general population were retrieved from the Dutch Comprehensive Cancer Registry. Outcome measures were defined as standardized incidence ratio and incidence rate per 100,000 person-years. RESULTS: Three hundred ninety-four patients (58% men; mean age at liver transplantation, 46.6 y) were included in the 1986 to 2007 period. Bowel investigation before liver transplantation had been performed in 73% of patients. Median follow-up was 5.1 years (range, 0.25-20 y). The mean age at the end of follow-up was 52 years (SD, 13 y). Colorectal carcinoma was diagnosed in four patients (1%) during follow-up. The overall standardized incidence ratio for colorectal carcinoma in post-liver transplant recipients was 2.16 (95% CI: 0.81-5.76) compared with the general population and 1.26 (95% CI: 0.31-5.03) for nonprimary sclerosing cholangitis post-liver transplant recipients. CONCLUSION: This study suggests that the incidence of colorectal carcinoma is not increased in non-primary sclerosing cholangitis post-liver transplantation compared with the general population. A more intense colorectal carcinoma surveillance program based on this result remains controversial in nonprimary sclerosing cholangitis post-liver transplant recipients.

Immunosuppressive drug withdrawal late after liver transplantation improves the lipid profile and reduces infections.

BACKGROUND: Treatment with immunosuppressive drugs (IS) after transplantation is accompanied by severe side effects. A limited number of studies have investigated the effect of IS withdrawal on IS-related comorbidities after liver transplantation (LTx) and the results are contradictory. PATIENTS AND METHODS: We determined in a retrospective case-control study the clinical effects of complete IS withdrawal in operationally tolerant (TOL) LTx recipients who discontinued IS 10.8 ± 5.1 years after LTx (n = 13) compared with a completely matched control (CTRL) group with a regular IS regimen (n = 22). TOL recipients have been IS and rejection free for 4.0 ± 2.8 years. RESULTS: IS withdrawal in TOL recipients resulted in lower low-density lipoprotein levels (P = 0.027), whereas this was not observed in the CTRL group. Furthermore, persistent infections in individual recipients were resolved successfully by IS withdrawal. TOL recipients also had significantly fewer de novo infections after IS withdrawal (TOL pre vs. post withdrawal P = 0.0247) compared with recipients continued on IS during the same follow-up period (post withdrawal TOL vs. CTRL P = 0.044). Unfortunately, no improvement in kidney function, and lower rates of de novo occurrences of diabetes, hypertension, cardiovascular diseases, and malignancies were observed in the TOL group after IS withdrawal compared with the CTRL group during the same follow-up time period. CONCLUSION: IS withdrawal late after LTx reduces infection rates and low-density lipoprotein levels, but other IS-related side effects persist late after LTx. An accurate tolerance immune profile enabling identification of tolerant LTx recipients eligible for safe IS withdrawal earlier after transplantation is needed to prevent the development of irreversible IS-related side effects.