Summary
Background
Adefovir and tenofovir are nucleotide analogues used as long‐term therapy of chronic hepatitis B. Side effects are few, but prolonged and high‐dose therapy has been associated with ...proximal renal tubular dysfunction (RTD).
Aim
To assess the incidence of RTD during long‐term nucleotide therapy of chronic hepatitis B.
Methods
A total of 51 patients being treated at the Clinical Center, National Institutes of Health were studied. Diagnosis of RTD required de novo appearance of at least three of five features: hypophosphataemia, hypouricaemia, serum creatinine elevation, proteinuria or glucosuria.
Results
Among 51 patients treated for 1–10 (mean 7.4) years with adefovir (n = 42), tenofovir (n = 4) or adefovir followed by tenofovir (n = 5), 7 (14%) developed RTD. Time to onset ranged from 22 to 94 (mean 49) months with an estimated 10‐year cumulative rate of 15%. All seven had low urinary percent maximal tubular reabsorption of phosphate (<82%). Patients with RTD were older (58 vs. 44 years; P = 0.01) and had lower baseline glomerular filtration rates (82 vs. 97 cc/min; P = 0.08) compared to those without; but did not differ in other features. Six patients with RTD were switched to entecavir, all subsequently had improvements in serum phosphate (2.0–3.0 mg/dL), creatinine (1.6–1.1 mg/dL), uric acid (2.7–3.8 mg/dL) and proteinuria.
Conclusions
Renal tubular dysfunction develops in 15% of patients treated with adefovir or tenofovir for 2–9 years and is partially reversible with change to other antivirals. Monitoring for serum phosphate, creatinine and urinalysis is prudent during long‐term adefovir and tenofovir therapy.
Summary
Background
Chronic delta hepatitis virus (HDV) infection rapidly progresses to cirrhosis. Treatment with peginterferon for up to 2 years is often without durable response.
Aim
To examine the ...efficacy and safety of long‐term peginterferon in achieving a durable response.
Methods
Treatment was initiated with 180 μg/week of peginterferon alfa‐2a with titration to a maximal tolerable dose, for up to 5 years. Liver biopsies and hepatic venous pressure gradients (HVPG) were evaluated at baseline, 1, 3 and 5 years. The primary endpoint was histological improvement or loss of serum HDV and HBsAg at 3 years.
Results
Thirteen patients were treated for a median of 140 weeks (6–260) with an average peginterferon dose of 180 μg/week (90–270). At baseline, most had advanced disease (median Ishak fibrosis = 3) with portal hypertension (HVPG = 10.2 ± 6 mmHg). Five of 13 patients (39%) achieved the primary endpoint, with three seroconverting for HBsAg after 24, 37 and 202 weeks of treatment. Histological inflammation improved after 1 year, (median HAI: 10 vs. 7, P = 0.01) with persistence in 4/5 patients at 3 years (median HAI: 7.5). Greatest improvements occurred in the first year. Baseline bilirubin and HBsAg levels were significantly lower in virological responders than nonresponders. After 12 weeks, virological responders had a significant decline in HBsAg (1.5 log10 IU/mL, P = 0.05).
Conclusion
Despite increased doses and duration of therapy, treatment of chronic HDV with peginterferon remains unsatisfactory. Quantitative measures of HBsAg may be an important biomarker of early response to peginterferon therapy in chronic delta hepatitis virus infection.
Summary
Background Non‐alcoholic steatohepatitis (NASH) is a form of progressive fatty liver disease that is strongly associated with insulin resistance, which suggests that insulin sensitizing ...agents such as metformin may be beneficial for NASH.
Aim To assess the effects of metformin on insulin sensitivity, body composition, serum alanine aminotransferase (ALT) levels and liver histology in patients with NASH.
Methods Patients underwent liver biopsy, metabolic profiling and imaging studies before and at the end 48 weeks of metformin (2000 mg/day) therapy. The primary endpoint was a three‐point improvement in the histological NASH activity index.
Results Of 28 patients enrolled, 26 (13 females; average age 44 years) completed 48 weeks of treatment and underwent repeat metabolic studies, imaging and liver biopsy. Thirty per cent achieved a histological response. Most patients lost weight, the average being 6 kg. There was a marked association between weight loss and improvements in NASH activity index and ALT levels (both, P < 0.01). Insulin sensitivity also improved, but the degree of change did not correlate with histological improvement.
Conclusion Metformin leads to improvements in liver histology and ALT levels in 30% of patients with NASH, probably by its effects in causing weight loss.
Summary
Drug‐induced liver injury (DILI) is often caused by innate and adaptive host immune responses. Characterization of inflammatory infiltrates in the liver may improve understanding of the ...underlying pathogenesis of DILI. This study aimed to enumerate and characterize leucocytes infiltrating liver tissue from subjects with acute DILI (n = 32) versus non‐DILI causes of acute liver injury (n = 25). Immunostains for CD11b/CD4 (Kupffer and T helper cells), CD3/CD20 (T and B cells) and CD8/CD56 T cytotoxic and natural killer (NK) cells were evaluated in biopsies from subjects with acute DILI, either immunoallergic (IAD) or autoimmune (AID) and idiopathic autoimmune (AIH) and viral hepatitis (VH) and correlated with clinical and pathological features. All biopsies showed numerous CD8+ T cells and macrophages. DILI cases had significantly fewer B lymphocytes than AIH and VH and significantly fewer NK cells than VH. Prominent plasma cells were unusual in IAD (three of 10 cases), but were associated strongly with AIH (eight of nine) and also observed in most with AID (six of nine). They were also found in five of 10 cases with VH. Liver biopsies from subjects with DILI were characterized by low counts of mature B cells and NK cells in portal triads in contrast to VH. NK cells were found only in cases of VH, whereas AIH and VH both showed higher counts of B cells than DILI. Plasma cells were associated most strongly with AIH and less so with AID, but were uncommon in IAD.
Adenosine deaminase 2 (ADA2) is an enzyme involved in purine metabolism and a growth factor that influences the development of endothelial cells and leukocytes. This study shows that defects in ADA2 ...cause recurrent fevers, vascular pathologic features, and mild immunodeficiency.
Patients with autoinflammatory disease sometimes present with clinical findings that encompass multiple organ systems.
1
Three unrelated children presented to the National Institutes of Health (NIH) Clinical Center with intermittent fevers, recurrent lacunar strokes, elevated levels of acute-phase reactants, livedoid rash, hepatosplenomegaly, and hypogammaglobulinemia. Collectively, these findings do not easily fit with any of the known inherited autoinflammatory diseases.
Hereditary or acquired vascular disorders can have protean manifestations yet be caused by mutations in a single gene. Diseases such as the Aicardi–Goutières syndrome,
2
,
3
polypoidal choroidal vasculopathy,
4
sickle cell anemia,
5
livedoid vasculopathy,
6
and the small-vessel vasculitides
7
,
8
are examples of systemic . . .
Multiple cell types infiltrate acutely rejecting renal allografts. Typically, monocytes and T cells predominate. Although T cells are known to be required for acute rejection, the degree to which ...monocytes influence this process remains incompletely defined. Specifically, it has not been established to what degree monocytes impact the clinical phenotype of rejection or how their influence compares to that of T cells. We therefore investigated the relative impact of T cells and monocytes by correlating their presence as measured by immunohistochemical staining with the magnitude of the acute change in renal function at the time of biopsy in 78 consecutive patients with histological acute rejection. We found that functional impairment was strongly associated with the degree of overall cellular infiltration as scored using Banff criteria. However, when cell types were considered, monocyte infiltration was quantitatively associated with renal dysfunction while T‐cell infiltration was not. Similarly, renal tubular stress, as indicated by HLA‐DR expression, increased with monocyte but not T‐cell infiltration. These data suggest that acute allograft dysfunction is most closely related to monocyte infiltration and that isolated T‐cell infiltration has less acute functional impact. This relationship may be useful in assigning acute clinical relevance to biopsy findings.
In analyzing the characteristics associated with functionally significant human acute renal allograft rejection, the authors find that monocyte content and renal tubular HLA‐DR expression are strongly related to the clinical dysfunction associated with a rejection episode.
Summary
Background
Non‐alcoholic steatohepatitis (NASH) is a common cause of serum alanine aminotransferase (ALT) elevations and chronic liver disease, but it is unclear how well ALT elevations ...reflect the liver injury.
Aim
To assess how well changes in ALT elevations reflect improvements in liver histology in response to vitamin E therapy.
Methods
The vitamin E and placebo arms of the Pioglitazone vs. Vitamin E vs. Placebo in Non‐alcoholic Steatohepatitis (PIVENS) trial were reassessed for associations among changes in ALT levels, body weight and liver histology. An ALT response was defined as a decrease to ≤40 U/L and by ≥30% of baseline. Liver biopsies taken before and after treatment were scored for non‐alcoholic fatty liver disease activity (NAS) and fibrosis.
Results
ALT responses were more frequent among vitamin E (48%) than placebo (16%) recipients (P < 0.001). Among vitamin E recipients, ALT responses were associated with decreases in NAS (P < 0.001), but not fibrosis scores (P = 0.34), whereas among placebo recipients, ALT responses were associated with significant decreases in both (P < 0.05). Weight loss (≥2 kg) was also associated with ALT response (P < 0.001), improvements in NAS (P < 0.001) and fibrosis (P < 0.02), but vitamin E had an added effect both with and without weight loss. Weight gain (≥2 kg) was associated with lack of ALT response and worsening NAS and fibrosis scores in patients not on vitamin E.
Conclusions
Decrease of ALT levels to normal in patients with NASH is usually associated with improved histological activity. Management should stress the value of weight loss and strongly discourage weight gain. Vitamin E can improve both ALT levels and histology with and without weight loss. Clinical Trial Number: NCT00063622.
Summary
Background
Although the short‐term benefits of a sustained virological response (SVR) to interferon‐based therapies of chronic hepatitis C (CHC) are well known, the long‐term consequences of ...SVR are less clear.
Aim
To assess changes in markers of disease activity and fibrosis in patients followed up to 23 years post‐SVR.
Methods
The first 103 SVR patients (from 1984 to 2003) at the National Institutes of Health Clinical Center were evaluated. Serum markers before treatment and at the last visit were compared. Evaluations after 2007 included transient elastography (TE).
Results
Of 103 patients, three subsequently relapsed 0.7, 6.3 and 6.5 years post therapy. The remaining 100 patients (56 men, mean age 56 years) maintained SVR at final follow‐up. No patients developed hepatic decompensation, but one with pre‐treatment cirrhosis died 12 years post SVR of hepatocellular carcinoma. In comparison to pre‐treatment values, markers improved at follow‐up, including mean ALT (152–27 U/L), AST (87–24 U/L), alkaline phosphatase (78–69 U/L), IgG (1463–1113 mg/dL), platelet count (209 000–239 000/μL) and AST to platelet count ratio index (APRI: 1.31–0.33). TE was performed in 69 patients and was normal (<7.0 kPA) in 60%, moderately elevated (7.1–13.8) in 31% and cirrhotic range (>13.8) in 9%. TE and platelet counts at follow‐up correlated with fibrosis on pre‐treatment liver biopsy (P < 0.001).
Conclusions
In 97% of patients with CHC, SVR is durable without evidence of disease progression, although some degree of hepatic fibrosis may persist and patients with pre‐treatment cirrhosis are at continuing low risk for hepatocellular carcinoma.
Cooperative social interaction is critical for human social development and learning. Despite the importance of social interaction, previous neuroimaging studies lack two fundamental components of ...everyday face-to-face interactions: contingent responding and joint attention. In the current studies, functional MRI data were collected while participants interacted with a human experimenter face-to-face via live video feed as they engaged in simple cooperative games. In Experiment 1, participants engaged in a live interaction with the experimenter (“Live”) or watched a video of the same interaction (“Recorded”). During the “Live” interaction, as compared to the Recorded conditions, greater activation was seen in brain regions involved in social cognition and reward, including the right temporoparietal junction (rTPJ), anterior cingulate cortex (ACC), right superior temporal sulcus (rSTS), ventral striatum, and amygdala. Experiment 2 isolated joint attention, a critical component of social interaction. Participants either followed the gaze of the live experimenter to a shared target of attention (“Joint Attention”) or found the target of attention alone while the experimenter was visible but not sharing attention (“Solo Attention”). The right temporoparietal junction and right posterior STS were differentially recruited during Joint, as compared to Solo, attention. These findings suggest the rpSTS and rTPJ are key regions for both social interaction and joint attention. This method of allowing online, contingent social interactions in the scanner could open up new avenues of research in social cognitive neuroscience, both in typical and atypical populations.
Composite tissue allotransplantation (CTA) is a recently introduced option for limb replacement and reconstruction of tissue defects. As with other allografts, CTA can undergo immune‐mediated ...rejection; therefore standardized criteria are required for characterizing and reporting severity and types of rejection. This article documents the conclusions of a symposium on CTA rejection held at the Ninth Banff Conference on Allograft Pathology in La‐Coruňa, Spain, on 26 June 2007, and proposes a working classification, the Banff CTA‐07, for the categorization of CTA rejection. This classification was derived from a consensus discussion session attended by the first authors of three published classification systems, pathologists and researchers from international centers where clinical CTA has been performed. It was open to all attendees to the Banff conference. To the extent possible, the format followed the established National Institutes of Health (NIH) guidelines on Consensus Development Programs. By consensus, the defining features to diagnose acute skin rejection include inflammatory cell infiltration with involvement of epidermis and/or adnexal structures, epithelial apoptosis, dyskeratosis and necrosis. Five grades of severity of rejection are defined. This classification refines proposed schemas, represents international consensus on this topic, and establishes a working collective classification system for CTA reporting of rejection in skin‐containing CTAs.
This report documents the conclusions of an international symposium on Composite Tissue Allograft (CTA) rejection held at the Ninth Banff Conference on Allograft Pathology in La‐Coruna, Spain on June 26, 2007 and proposes a working classification, the Banff CTA‐07, for the categorization of CTA rejection.
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