Acute intermittent porphyria results in excess activity of ALA synthase and overproduction of neurotoxic metabolites that cause attacks of severe abdominal pain. Givosiran, an interfering RNA, blocks ...synthesis of the enzyme, reduces the attack rate, and has only mild-to-moderate side effects.
Hepatitis E virus is the aetiological agent of acute hepatitis E, a self-limiting disease prevalent in developing countries. Molecular analysis of viral genomic RNA from a chronically infected ...patient confirmed the recent discovery that chronic infection correlated with extensive diversification of the virus quasispecies: the hypervariable region of some virus genomes in this USA patient contained large continuous deletions and a minor proportion of genomes in faeces and serum had acquired a mammalian sequence that encoded 39 aa of S19 ribosomal protein fused to the virus non-structural protein. Genomes with this insert were selected during virus passage in cultured cells to become the predominant species, suggesting that the inserted sequence promoted virus growth. The results demonstrated that hepatitis E virus can mutate dramatically during a prolonged infection and suggests it may be important to prevent or cure chronic infections before new variants with unpredictable properties arise.
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.
Background/Aims: Non-alcoholic steatohepatitis (NASH) is increasingly recognized, and its pathogenesis is believed to involve increased oxidative stress. Elevated levels of serum ferritin and ...positive liver iron stains are often observed in patients with NASH, and the pathogenesis of liver injury due to iron is also thought to involve oxidative stress. The aim of this study was to determine whether there is an association of NASH and mutations in the HFE gene associated with hereditary hemochromatosis (HHC).
Methods: Clinical, laboratory, and histopathological data on all 57 subjects with a final diagnosis of NASH seen between August 1990 and August 1997 at our Liver Center were analyzed. Thirty-six Caucasian subjects (23 men) with NASH underwent mutational analyses of HFE gene mutations performed. The prevalence of HFE gene mutations was compared to that in 348 Caucasian normal controls. Data were analyzed by both parameteric and non-parametric methods with similar results.
Results: One subject (2.8%) with NASH was homozygous for the C282Y mutation and six (16.7%) were heterozygous, compared with 0% and 11.2%, respectively, of controls. Two (5.6%) subjects with NASH were homozygous for the H63D mutation and 16 (44.4%) were heterozygous, whereas 2.9% and 26.4%, respectively, of controls had these genotypes. The prevalence of heterozygosity (61.1%) for either mutation was significantly higher in subjects with NASH than in controls (38%) (
p=0.008), and the prevalence of homozygosity or heterozygosity combined in NASH subjects (69.4%) was significantly higher than for controls (40.5%,
p=0.001). Sex (63–67% male) and age at diagnosis of NASH did not differ between those with or without HFE mutations, but men with NASH were significantly more likely than women to have the H63D mutation (15/23
vs. 3/13,
p<0.05) Levels of serum ferritin, iron, transferrin saturation levels, and the degree of hepatic iron staining were significantly higher (
p<0.05) in subjects with NASH who carried an HFE mutation than in those without. Differences in hepatic iron concentrations or hepatic iron indices between NASH subjects with and without HFE mutations were not significant. Those with C282Y mutations had significantly more hepatic fibrosis than those without (
p<0.05). Those with HFE mutations had significantly higher levels of serum ALT (90±11 mean±SE) than those without (55±6;
p=0.02).
Conclusion: The prevalences of the HFE gene mutations associated with hereditary hemochromatosis are increased among North American subjects with NASH.
The natural history, prognosis, and clinical significance of chronic hepatitis C are highly variable and somewhat controversial. The purpose of this study was to evaluate the effect of chronic ...hepatitis C infection on patients' perceptions of health‐related quality of life (HRQOL) and to evaluate whether treatment with interferon improves HRQOL. A total of 642 patients with compensated liver disease who were enrolled in a multicenter trial of interferon therapy for chronic hepatitis C had evaluation of HRQOL using the SF‐36 and other instruments derived from the Medical Outcomes Study (MOS). These instruments were self‐administered by patients at baseline and at the end of a 24‐week post‐treatment observation period after 24 weeks of interferon treatment. Patients with chronic hepatitis C were compared with healthy controls (n = 750) selected from a representative sample of adults in the United States. Unadjusted and age/gender‐adjusted results were similar, as were analyses using parametric or nonparametric methods. Compared with healthy controls, patients with chronic hepatitis C at baseline had lower HRQOL on all eight scales of the SF‐36 (P < .001 for all). Patients without cirrhosis (n = 284 ) showed similar although slightly smaller differences. The differences were highly significant, clinically and socially relevant, and greatest for those scales that were more reflective of physical than mental or emotional disease. Patients who had a sustained viral response to interferon therapy (n = 41) exhibited marked improvements in HRQOL, and these improvements exceeded those of nonresponders on 13 of 14 HRQOL scales (8 were statistically significant). Similar improvements were noted in patients with sustained biochemical responses. The authors concluded that patients with chronic hepatitis C with or without cirrhosis have markedly reduced HRQOL. Patients who had a sustained response (virological or biochemical) to interferon therapy experienced significant improvements in perceived wellness and functional status. Successful interferon therapy provides meaningful improvements in HRQOL in patients with chronic hepatitis C.
Summary
Background
Idiosyncratic drug‐induced liver injury (DILI) is a complex disorder that is difficult to predict, diagnose and treat.
Aim
To describe the global serum proteome of patients with ...DILI and controls.
Methods
A label‐free, mass spectrometry‐based quantitative proteomic approach was used to explore protein expression in serum samples from 74 DILI patients (collected within 14 days of DILI onset) and 40 controls. A longitudinal analysis was conducted in a subset of 21 DILI patients with available 6‐month follow‐up serum samples.
Results
Comparison of DILI patients based on pattern, severity and causality assessment of liver injury revealed many differentially expressed priority 1 proteins among groups. Expression of fumarylacetoacetase was correlated with alanine aminotransferase (ALT; r = 0.237; P = 0.047), aspartate aminotransferase (AST; r = 0.389; P = 0.001) and alkaline phosphatase (r = −0.240; P = 0.043), and this was the only protein with significant differential expression when comparing patients with hepatocellular vs. cholestatic or mixed injury. In the longitudinal analysis, expression of 53 priority 1 proteins changed significantly from onset of DILI to 6‐month follow‐up, and nearly all proteins returned to expression levels comparable to control subjects. Ninety‐two serum priority 1 proteins with significant differential expression were identified when comparing the DILI and control groups. Pattern analysis revealed proteins that are components of inflammation, immune system activation and several hepatotoxicity‐specific pathways. Apolipoprotein E expression had the greatest power to differentiate DILI patients from controls (89% correct classification; AUROC = 0.97).
Conclusion
This proteomic analysis identified differentially expressed proteins that are components of pathways previously implicated in the pathogenesis of idiosyncratic drug‐induced liver injury.
Background & Aims
Upregulation of hepatic delta‐aminolevulinic acid synthase 1 with accumulation of potentially toxic heme precursors delta‐aminolevulinic acid and porphobilinogen is fundamental to ...the pathogenesis of acute hepatic porphyria. Aims: evaluate long‐term efficacy and safety of givosiran in acute hepatic porphyria.
Methods
Interim analysis of ongoing ENVISION study (NCT03338816), after all active patients completed their Month 24 visit. Patients with acute hepatic porphyria (≥12 years) with recurrent attacks received givosiran (2.5 mg/kg monthly) (n = 48) or placebo (n = 46) for 6 months (double‐blind period); 93 received givosiran (2.5 mg or 1.25 mg/kg monthly) in the open‐label extension (continuous givosiran, n = 47/48; placebo crossover, n = 46/46). Endpoints included annualized attack rate, urinary delta‐aminolevulinic acid and porphobilinogen levels, hemin use, daily worst pain, quality of life, and adverse events.
Results
Patients receiving continuous givosiran had sustained annualized attack rate reduction (median 1.0 in double‐blind period, 0.0 in open‐label extension); in placebo crossover patients, median annualized attack rate decreased from 10.7 to 1.4. Median annualized days of hemin use were 0.0 (double‐blind period) and 0.0 (open‐label extension) for continuous givosiran patients and reduced from 14.98 to 0.71 for placebo crossover patients. Long‐term givosiran led to sustained lowering of delta‐aminolevulinic acid and porphobilinogen and improvements in daily worst pain and quality of life. Safety findings were consistent with the double‐blind period.
Conclusions
Long‐term givosiran has an acceptable safety profile and significantly benefits acute hepatic porphyria patients with recurrent attacks by reducing attack frequency, hemin use, and severity of daily worst pain while improving quality of life.
Background and Aims
Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, ...debilitating chronic symptoms, and long‐term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients.
Approach and Results
EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0‐52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median range annualized attack rate 2.0 0.0‐37.0). Elevated levels of hepatic δ‐aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ‐aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization.
Conclusions
Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day‐to‐day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies.
Current blood biomarkers are suboptimal in detecting drug‐induced liver injury (DILI) and predicting its outcome. We sought to characterize the natural variabilty and performance characteristics of ...14 promising DILI biomarker candidates. Serum or plasma from multiple cohorts of healthy volunteers (n = 192 and n = 81), subjects who safely took potentially hepatotoxic drugs without adverse effects (n = 55 and n = 92) and DILI patients (n = 98, n = 28, and n = 143) were assayed for microRNA‐122 (miR‐122), glutamate dehydrogenase (GLDH), total cytokeratin 18 (K18), caspase cleaved K18, glutathione S‐transferase α, alpha‐fetoprotein, arginase‐1, osteopontin (OPN), sorbitol dehydrogenase, fatty acid binding protein, cadherin‐5, macrophage colony‐stimulating factor receptor (MCSFR), paraoxonase 1 (normalized to prothrombin protein), and leukocyte cell‐derived chemotaxin‐2. Most candidate biomarkers were significantly altered in DILI cases compared with healthy volunteers. GLDH correlated more closely with gold standard alanine aminotransferase than miR‐122, and there was a surprisingly wide inter‐ and intra‐individual variability of miR‐122 levels among healthy volunteers. Serum K18, OPN, and MCSFR levels were most strongly associated with liver‐related death or transplantation within 6 months of DILI onset. Prediction of prognosis among DILI patients using the Model for End‐Stage Liver Disease was improved by incorporation of K18 and MCSFR levels. Conclusion: GLDH appears to be more useful than miR‐122 in identifying DILI patients, and K18, OPN, and MCSFR are promising candidates for prediction of prognosis during an acute DILI event. Serial assessment of these biomarkers in large prospective studies will help further delineate their role in DILI diagnosis and management.
PDF
