ATP7B Genotype and Chronic Liver Disease Treatment Outcomes in Wilson Disease: Worse Survival With Loss-of-Function Variants.

BACKGROUND AND AIMS: Although a good genotype-phenotype correlation has not been established in Wilson disease (WD), patients with loss-of-function (LOF) ATP7B variants demonstrate different clinical and biochemical characteristics. We aim to describe long-term treatment outcomes in the chronic liver disease (CLD) phenotype and evaluate an association with LOF variants. METHODS: This was a single-center retrospective review of WD patients with at least 1 variant in ATP7B. Demographic, biochemical, genetic, and clinical parameters were obtained. The composite clinical endpoint of liver transplantation or death was used for probands with CLD phenotype on chelators. RESULTS: Of 117 patients with hepatic WD: 71 had CLD, 27 had fulminant hepatic failure requiring urgent liver transplantation, and 19 were diagnosed through family screening. Median age at diagnosis was 13.1 (interquartile range, 9.7-17.6) years. In total, 91 variants in ATP7B were identified in the study population. At least 1 LOF variant was present in 60 (51.3%) patients. During median follow-up of 10.7 (interquartile range, 6.7-18.9) years, 10 (14.1%) of the probands with CLD reached the composite endpoint. There was a worse transplant-free survival for patients prescribed chelation therapy in patients with at least 1 LOF variant (P = .03). CONCLUSIONS: Patients with WD and CLD phenotype on chelators, who have at least 1 LOF variant in ATP7B, have a worse prognosis during long-term follow up. This subgroup of patients requires close monitoring for signs of progressive liver disease. Sequencing of ATP7B may be used in the diagnosis of WD, and in addition, it may provide useful prognostic information for patients with hepatic WD.

Catatonia: demographic, clinical and laboratory associations.

BACKGROUND: Catatonia, a severe neuropsychiatric syndrome, has few studies of sufficient scale to clarify its epidemiology or pathophysiology. We aimed to characterise demographic associations, peripheral inflammatory markers and outcome of catatonia. METHODS: Electronic healthcare records were searched for validated clinical diagnoses of catatonia. In a case-control study, demographics and inflammatory markers were compared in psychiatric inpatients with and without catatonia. In a cohort study, the two groups were compared in terms of their duration of admission and mortality. RESULTS: We identified 1456 patients with catatonia (of whom 25.1% had two or more episodes) and 24 956 psychiatric inpatients without catatonia. Incidence was 10.6 episodes of catatonia per 100 000 person-years. Patients with and without catatonia were similar in sex, younger and more likely to be of Black ethnicity. Serum iron was reduced in patients with catatonia [11.6 v. 14.2 µmol/L, odds ratio (OR) 0.65 (95% confidence interval (CI) 0.45-0.95), p = 0.03] and creatine kinase was raised [2545 v. 459 IU/L, OR 1.53 (95% CI 1.29-1.81), p < 0.001], but there was no difference in C-reactive protein or white cell count. N-Methyl-d-aspartate receptor antibodies were significantly associated with catatonia, but there were small numbers of positive results. Duration of hospitalisation was greater in the catatonia group (median: 43 v. 25 days), but there was no difference in mortality after adjustment. CONCLUSIONS: In the largest clinical study of catatonia, we found catatonia occurred in approximately 1 per 10 000 person-years. Evidence for a proinflammatory state was mixed. Catatonia was associated with prolonged inpatient admission but not with increased mortality.

Synonymous mutation in adenosine triphosphatase copper-transporting beta causes enhanced exon skipping in Wilson disease.

Wilson disease (WD) is caused by biallelic pathogenic variants in adenosine triphosphatase copper-transporting beta (ATP7B); however, genetic testing identifies only one or no pathogenic ATP7B variant in a number of patients with WD. Synonymous single-nucleotide sequence variants have been recognized as pathogenic in individual families. The aim of the present study was to evaluate the prevalence and disease mechanism of the synonymous variant c.2292C>T (p.Phe764=) in WD. A cohort of 280 patients with WD heterozygous for a single ATP7B variant was investigated for the presence of c.2292C>T (p.Phe764=). In this cohort of otherwise genetically unexplained WD, the allele frequency of c.2292C>T (p.Phe764=) was 2.5% (14 of 560) compared to 7.1 × 10-6 in the general population (2 of 280,964 in the Genome Aggregation Database; p < 10-5 ; Fisher exact test). In an independent United Kingdom (UK) cohort, 2 patients with WD homozygous for p.Phe764= were identified. RNA analysis of ATP7B transcripts from patients homozygous or heterozygous for c.2292C>T and control fibroblasts showed that this variant caused high expression of an ATP7B transcript variant lacking exon 8. Conclusion: The synonymous ATP7B variant c.2292C>T (p.Phe764=) causes abnormal messenger RNA processing of ATP7B transcripts and is associated with WD in compound heterozygotes and homozygotes.

Modern Outcomes Following Treatment of Hepatocellular Carcinoma in Hereditary Hemochromatosis: A Matched Cohort Study.

OBJECTIVE: Hepatocellular carcinoma (HCC) is a complication of the common genetic condition hereditary hemochromatosis (HH). It is unknown whether HH as an etiology of liver disease impacts the outcome. We compared the results of liver transplantation (LT), surgical resection and locoregional therapies in a matched cohort study and investigated whether HH as an etiology has an impact on survival. MATERIALS AND METHODS: Consecutive patients with HH and HCC (2000 to 2015) were compared with age, sex and Barcelona Clinic Liver Cancer (BCLC) stage-matched non-HH HCC cases. Patients were offered curative or noncurative treatment according to BCLC stage and Milan criteria. The primary endpoint was all-cause mortality. RESULTS: A total of 102 patients (52 HH; total cohort median age: 67 [44 to 78] y, 97% male, Model for End-stage Liver Disease: 9 [5 to 31]) were studied with a median follow-up of 22 (3 to 126) months. Of the HH cases, the median serum ferritin at diagnosis of HCC was 326 (27 to 5718) µg/L and α-fetoprotein 33 (2 to 197,926) kIU/L. Five-year survival for HH patients receiving curative therapy was 77% (80% for LT, 67% for resection/radiofrequency ablation), and 15% (23% for transarterial chemoembolization) for those undergoing noncurative therapy. Survival for HH patients compared with controls was similar (hazard ratio=0.949; P=0.839). On multivariate Cox regression survival analysis, BCLC stage, and diagnosis of ischemic heart disease (but not HH diagnosis) were independently associated with reduced survival. CONCLUSIONS: Patients with HCC and HH can achieve comparable survival rates following curative or LRT modalities to other liver diseases. The BCLC staging system accurately stratifies survival and excellent 5-year survival is possible following LT in selected patients.

Interim assessment of liver damage in patients with sickle cell disease using new non-invasive techniques.

We explored transient elastography (TE) and enhanced liver fibrosis (ELF™ ) score with standard markers of liver function to assess liver damage in 193 well patients with sickle cell disease (SCD). Patients with HbSS or HbSß0 thalassaemia (sickle cell anaemia, SCA; N = 134), had significantly higher TE results and ELF scores than those with HbSC (N = 49) disease (TE, 6·8 vs. 5·3, P < 0·0001 and ELF, 9·2 vs. 8·6 P < 0·0001). In SCA patients, TE and ELF correlated significantly with age and all serum liver function tests (LFTs). Additionally, (weak) positive correlation was found with lactate dehydrogenase (TE: r = 0·24, P = 0·004; ELF: r = 0·26 P = 0·002), and (weak) negative correlation with haemoglobin (TE: r = -0·25, P = 0·002; ELF: r = -0·25 P = 0·004). In HbSC patients, correlations were weaker or not significant between TE or ELF, and serum LFTs. All markers of iron loading correlated with TE values when corrected for sickle genotype (serum ferritin, ß = 0·25, P < 0·0001, total blood transfusion units, ß = 0·25, P < 0·0001 and LIC ß = 0·32, P = 0·046). The exploratory study suggests that, while TE could have a role, the utility of ELF score in monitoring liver damage in SCD, needs further longitudinal studies.

Expression and cellular localization of hepcidin mRNA and protein in normal rat brain.

BACKGROUND: Hepcidin is a peptide hormone belonging to the defensin family of cationic antimicrobial molecules that has an essential role in systemic iron homeostasis. The peptide is synthesised by hepatocytes and transported in the circulation to target tissues where it regulates the iron export function of the ferrous iron permease, ferroportin. In the brain hepcidin protein has been identified using immuno-histochemistry and mRNA by real-time PCR but not by in situ hybridisation raising the question of whether there is measurable transcription of the hepcidin gene in the central nervous system. Alternatively hepcidin could be transported as a hormone to the brain via the circulation. RESULTS: By RT-PCR hepcidin mRNA was present at low level throughout normal rat brain while in situ hybridisation to detect low-abundant mRNA revealed that transcripts were restricted to endothelium of blood vessels and choroid plexus. In contrast, hepcidin protein analysed by immuno-histochemistry was highly expressed in blood vessels, in endothelium and in pericytes. Hepcidin was also present in glial cells and in the olfactory bulb, sub-ventricular zone and dentate gyrus, areas where neurogenesis and synaptic plasticity are maintained throughout adult life. The hepcidin species identified by Western blotting in sub-ventricular zone, cortex and hippocampus migrated as a ~2.8 kDa band, identical in size to hepcidin present in normal rat serum suggesting that hepcidin in brain was the full-length biologically active 25 amino acid peptide. Hepcidin co-localised with ferroportin in ependymal cells of the sub-ventricular zone and in the corpus callosum consistent with a regulatory role in iron metabolism at these sites. CONCLUSIONS: Hepcidin protein was widely expressed in brain parenchyma while levels of hepcidin gene transcription appeared to be below the limits of detection of the in situ hybridisation probes. This disparity suggests that not all hepcidin in the brain is transcribed in situ and may originate in part outside the brain. The properties of hepcidin as a cationic peptide hormone are reflected in the finding of hepcidin in the walls of blood vessels and in pericytes and glia, cells that may be involved in transporting the peptide into brain interstitium.

How we treat sickle hepatopathy and liver transplantation in adults.

Sickle cell disease (SCD) has evolved into a debilitating disorder with emerging end-organ damage. One of the organs affected is the liver, causing "sickle hepatopathy," an umbrella term for a variety of acute and chronic pathologies. Prevalence of liver dysfunction in SCD is unknown, with estimates of 10%. Dominant etiologies include gallstones, hepatic sequestration, viral hepatitis, and sickle cell intrahepatic cholestasis (SCIC). In addition, causes of liver disease outside SCD must be identified and managed. SCIC is an uncommon, severe subtype, with outcome of its acute form having vastly improved with exchange blood transfusion (EBT). In its chronic form, there is limited evidence for EBT programs as a therapeutic option. Liver transplantation may have a role in a subset of patients with minimal SCD-related other organ damage. In the transplantation setting, EBT is important to maintain a low hemoglobin S fraction peri- and posttransplantation. Liver dysfunction in SCD is likely to escalate as life span increases and patients incur incremental transfusional iron overload. Future work must concentrate on not only investigating the underlying pathogenesis, but also identifying in whom and when to intervene with the 2 treatment modalities available: EBT and liver transplantation.

The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer's disease.

BACKGROUND: The pathological features of the common neurodegenerative conditions, Alzheimer's disease (AD), Parkinson's disease and multiple sclerosis are all known to be associated with iron dysregulation in regions of the brain where the specific pathology is most highly expressed. Iron accumulates in cortical plaques and neurofibrillary tangles in AD where it participates in redox cycling and causes oxidative damage to neurons. To understand these abnormalities in the distribution of iron the expression of proteins that maintain systemic iron balance was investigated in human AD brains and in the APP-transgenic (APP-tg) mouse. RESULTS: Protein levels of hepcidin, the iron-homeostatic peptide, and ferroportin, the iron exporter, were significantly reduced in hippocampal lysates from AD brains. By histochemistry, hepcidin and ferroportin were widely distributed in the normal human brain and co-localised in neurons and astrocytes suggesting a role in regulating iron release. In AD brains, hepcidin expression was reduced and restricted to the neuropil, blood vessels and damaged neurons. In the APP-tg mouse immunoreactivity for ferritin light-chain, the iron storage isoform, was initially distributed throughout the brain and as the disease progressed accumulated in the core of amyloid plaques. In human and mouse tissues, extensive AD pathology with amyloid plaques and severe vascular damage with loss of pericytes and endothelial disruption was seen. In AD brains, hepcidin and ferroportin were associated with haem-positive granular deposits in the region of damaged blood vessels. CONCLUSION: Our results suggest that the reduction in ferroportin levels are likely associated with cerebral ischaemia, inflammation, the loss of neurons due to the well-characterised protein misfolding, senile plaque formation and possibly the ageing process itself. The reasons for the reduction in hepcidin levels are less clear but future investigation could examine circulating levels of the peptide in AD and a possible reduction in the passage of hepcidin across damaged vascular endothelium. Imbalance in the levels and distribution of ferritin light-chain further indicate a failure to utilize and release iron by damaged and degenerating neurons.

The association of pretransplant ferritin level with waiting list and post-transplant survival. Does ferritin actually predict outcome?

Recent data suggest an association of serum ferritin (SF) with waiting list (WL) and postliver transplant (LT) outcomes. To assess the predictive capacity of SF on pre- and post-LT outcomes, and to identify whether recipient or donor liver siderosis is associated with post-LT survival; a retrospective analysis of 1079 patients assessed for first LT, 2000-2007 was performed. Iron deposition in the liver tissue was assessed using a semi-quantitative grading system. Median age was 54 (18-82) years and 67% were male. Seventeen per cent had hepatocellular carcinoma (HCC). Median Model for End-stage Liver Disease MELD score was 14 (6-40), ferritin was 174 µg/l (4-4597) with 36.5% had a SF ≥ µg/l. Age (OR = 1.028) and MELD score (OR = 1.158) were independently associated with WL mortality (P < 0.001), whilst SF was not (P = NS). Age (OR = 1.018), HCC (OR = 1.542) and cold ischemia time (CIT) ≥ 10 h (OR = 1.418) were independently associated with post-LT survival (P < 0.05). Explant siderosis grade <2 was seen in 376 (71.7%) patients. Patients with explant siderosis grade ≥ 2 had inferior 12-month post-LT survival (P = 0.030). Presence of graft siderosis (15.8% of patients) was not associated with survival. In conclusion, we found a limited role for SF as a prognostic indicator for pre- or post-transplant survival.

Two novel mutations in the L ferritin coding sequence associated with benign hyperferritinaemia unmasked by glycosylated ferritin assay.

Investigating persistent hyperferritinaemia without apparent iron overload is challenging. Even when inflammation, cirrhosis, Still's disease, fatty liver and malignancy are excluded, there remains a group of patients with unexplained hyperferritinaemia for whom rare forms of haemochromatosis (ferroportin disease) are a consideration. Preliminary results suggest that abnormal percentage glycosylation of serum ferritin is seen in some cases of genetically determined hyperferritinaemia. Serum ferritin is normally 50-81% glycosylated, but low glycosylation (20-42%) prevails in hereditary hyperferritinaemia cataract syndrome. This contrasts with hyperglycosylation (>90%) associated with the benign hyperferritinaemia related to missense L ferritin (p.Thr30Ile) mutation. Here, we describe two novel missense L ferritin variants also associated with hyperglycosylation, p.Gln26Ile and p.Ala27Val. Ferritin glycosylation, a comparatively simple measurement, can identify patients for DNA sequencing as hyperglycosylation (>90%) is associated with benign hyperferritinaemia and mutant L ferritin chain.

Peritoneal macrophages from patients with cirrhotic ascites show impaired phagocytosis and vigorous respiratory burst.

Cirrhotic patients (CPs) are susceptible to spontaneous bacterial peritonitis (SBP). Aim of this study was to examine if this susceptibility was related to peritoneal macrophages' (PMs) altered host defence. Absorbance of phagocytosed particles by PMs from CPs was lower than that of control (31.88% vs. 77.2%). Particle opsonisation increased the absorbance to 41% in CPs' PMs, and this value remains lower than the control; 77.2%. Respiratory burst (RB) was expressed as fluorescence index values, and these were higher in PMs from CPs than in controls (82 vs. 41, 73 vs. 26 and 71 vs. 26). IFN-γ made no further increase of RB values in PMs from CPs. CD14 expression was also higher in CPs' PMs. IFN-γ significantly downregulated CD14 expression in both CPs' PMs and control. Reduced phagocytosis by predominantly CD14-positive PMs from CPs could be related to intense RB. Findings suggest altered host defence that could contribute to susceptibility to SBP.

Quantitation of hepcidin in serum using ultra-high-pressure liquid chromatography and a linear ion trap mass spectrometer.

Hepcidin is a peptide hormone that functions as a key regulator of mammalian iron metabolism. Biological levels are increased in end-stage renal disease and during inflammation but suppressed in hemochromatosis. Thus hepcidin levels have diagnostic importance. This study describes the development of an analytical method for the quantitative determination of the concentration of hepcidin in clinical samples. The fragmentation of hepcidin was investigated using triple quadrupole and linear ion trap mass spectrometers. A standard quantity of a stable isotopically labelled hepcidin internal standard was added to serum samples. Extraction was performed by protein precipitation and weak cation-exchange magnetic nanoparticles. Chromatography was carried out on sub 2 microm particle stationary phase, using ultra-high-pressure liquid chromatography and a linear ion trap for quantitation. The lower limit of quantitation was 0.4 nmol/L with less than 20% accuracy and precision. The mean hepcidin concentration in sera for controls was 4.6 +/- 2.7 nmol/L, in patients with sickle cell disease, 7.0 +/- 8.9 nmol/L; in patients with end-stage renal disease, 30.5 +/- 15.7 nmol/L; and patients with penetrant hereditary hemochromatosis, 1.4 +/- 0.8 nmol/L.

Outcome of liver transplantation in hereditary hemochromatosis.

Hereditary hemochromatosis (HH) is a genetic disorder of iron metabolism. It is an uncommon indication for liver transplantation (LT). It has been suggested that patients who undergo LT for cirrhosis related to HH have higher morbidity and mortality from cardiac, infectious and malignant complications. The purpose of this retrospective review was to determine whether these observations hold true in the current era. We analysed the data of 22 patients who had LT for HH from 1996 to 2007 at our center. Thirteen patients had LT for complications of end-stage liver disease, seven for hepatocellular carcinoma (HCC) and two for subacute liver failure. Cofactors promoting liver disease were identified in 15 patients. Ten patients had iron reduction with venesection before transplantation. Patient and graft survival at 1 and 5 years were 80.7%, and 74% respectively. There were seven deaths after a median follow up of 46 months either because of multiorgan failure, or caused by HCC recurrence. Bacterial infections were the commonest cause of morbidity. Patients with HH remain at a higher risk of developing HCC. Infectious complications are common. Iron reduction with preoperative venesection reduces the risk of cardiac and infection complications postoperatively. Improved survival post-LT reflects changes in selection, disease modification through venesection, and improvement in immunosuppression.

Quantification of hepcidin using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Hepcidin is known to be a key systemic iron-regulatory hormone which has been demonstrated to be associated with a number of iron disorders. Hepcidin concentrations are increased in inflammation and suppressed in hemochromatosis. In view of the role of hepcidin in disease, its potential as a diagnostic tool in a clinical setting is evident. This study describes the development of a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) assay for the quantitative determination of hepcidin concentrations in clinical samples. A stable isotope labeled hepcidin was prepared as an internal standard and a standard quantity was added to urine samples. Extraction was performed with weak cation-exchange magnetic nanoparticles. The basic peptides were eluted from the magnetic nanoparticles using a matrix solution directly onto a target plate and analyzed by MALDI-TOF MS to determine the concentration of hepcidin. The assay was validated in charcoal stripped urine, and good recovery (70-80%) was obtained, as were limit of quantitation data (5 nmol/L), accuracy (RE <10%), precision (CV <21%), within -day repeatability (CV <13%) and between-day repeatability (CV <21%). Urine hepcidin levels were 10 nmol/mmol creatinine in healthy controls, with reduced levels in hereditary hemochromatosis (P < 0.000005) and elevated levels in inflammation (P < 0.0007). In summary a validated method has been developed for the determination of hepcidin concentrations in clinical samples.

Quantitation of hepcidin in human urine by liquid chromatography-mass spectrometry.

Hepcidin is a peptide hormone that functions as a key regulator of mammalian iron metabolism. Serum and urine levels are increased in inflammation and suppressed in hemochromatosis, and they may have diagnostic importance. This study describes the development and validation of an analytical method for the quantitative determination of the concentration of hepcidin in clinical samples. A stable, isotopically labeled internal standard, [15N,13C2]Gly12,20-hepcidin, was synthesized and a standard quantity was added to urine samples. Extraction was performed using weak cation exchange magnetic nanoparticles. An ion trap mass spectrometer was used to quantify hepcidin in the samples. The hepcidin assay was validated, and good recovery of hepcidin was obtained. The assay is accurate and precise. Urinary hepcidin levels of 3 to 9 nmol/mmol creatinine(-1) were found in healthy controls, with reduced levels in hemochromatosis (P<0.00006) and elevated levels in inflammation (P<0.00035). In sickle cell disease, a wide range was found, with the mean value not differing significantly from controls (P<0.26). In summary, a validated method has been developed for the quantitation of hepcidin using a stable, isotopically labeled internal standard and applied to determine the concentrations of hepcidin in the low nanomolar range in urine samples from patients and controls.

Evaluation of risk factors in the development of hepatocellular carcinoma in autoimmune hepatitis: Implications for follow-up and screening.

UNLABELLED: Hepatocellular carcinoma (HCC) has traditionally been considered a rare complication of cirrhosis secondary to autoimmune hepatitis (AIH), yet the true incidence remains unknown due to a lack of published data. Consequently, some professional guidelines do not mandate routine surveillance for HCC in this condition. Our aims were to evaluate the rate at which HCC develops among a large, prospectively obtained cohort of patients with AIH at a single center. Demographic, clinical, and laboratory indices associated with the development of HCC were also identified. HCC was discovered in 15 of 243 patients with AIH, all of whom had type 1 AIH equating to 1090 cases per 100,000 patient follow-up years. HCC occurred in the same proportion of females as males, 6.1% versus 6.4%, P = 0.95. HCC occurred more frequently in patients who had cirrhosis at presentation, 9.3% versus 3.4%, P = 0.048, or who had a variceal bleed as the index presentation of AIH, 20% versus 5.3%, P = 0.003. The median duration from time of confirmed cirrhosis to a diagnosis of HCC was 102.5 months, range 12-195 months. Median survival in patients whose HCC was diagnosed on surveillance was 19 months (range 6-36 months) compared with 2 months (range 0-14 months) for patients presenting symptomatically (P = 0.042). CONCLUSION: Cirrhosis in AIH is the sine qua non for HCC development, which subsequently occurs at a rate of 1.1% per year and affects men and women in equal proportions.

Post-prandial iron absorption in humans: comparison between HFE genotypes and iron deficiency anaemia.

BACKGROUND & AIMS: Measurement of serum iron increase after ingestion of a meal could be an efficient method of comparing post-prandial iron absorption between groups of individuals. We determined whether the rise in post-prandial serum iron is increased in fully treated patients with hereditary haemochromatosis (HFE C282Y+/+; HH) compared to iron deficiency anaemia (IDA), iron-replete heterozygous subjects (HFE C282Y+/-) and iron-replete controls (HFE C282Y-/-). METHODS: Serum iron increase was measured over 4h after a meal containing 13.1 mg non-haem iron. RESULTS: Post-prandial increase in serum iron was similar in treated HH versus IDA (P=0.54), but greater than control subjects (P<0.0001). In five HH patients, using (58)Fe as a tracer, the rate of iron absorption was increased (P<0.05) and serum non-transferrin bound iron showed a tendency to increase (P=0.06). Serum iron curves did not differ for heterozygous subjects and controls (P=0.65). CONCLUSIONS: Using the serum iron method we found a comparable increase in post-prandial iron absorption in treated HH and IDA compared with controls. While post-prandial iron absorption in the group heterozygous for the C282Y mutation was modestly increased relative to controls, this difference was not statistically significant.

Hepatic dysfunction in sickle cell disease: a new system of classification based on global assessment.

BACKGROUND & AIMS: Hepatic dysfunction in adults with sickle cell disease varies in character and severity from self-limited cholestasis to life-threatening acute liver failure and cirrhosis. Because previous attempts to describe patterns of liver disease have not reflected clinical experience, we aimed to characterize the presentation, clinicopathologic findings, and natural history of such patients. METHODS: We reviewed the clinical, laboratory, radiographic, and histologic features with the natural history of 38 patients (mean age, 33 years) with Hb SS, SC, or S-beta thalassemia referred to a tertiary liver center for assessment. RESULTS: Distinct disease patterns were identified that comprised massive hepatocellular necrosis (5%), acute severe sequestration and cholestasis in the context of sepsis (18%), cirrhosis (18%), chronic, fluctuating sequestration without cholestasis (21%), mechanical biliary obstruction (8%), siderosis without cirrhosis (8%), generalized cholangiopathy (8%), venous outflow obstruction (3%), and miscellaneous (11%). Of the 20 who required emergency admission, 8 did not survive their index admission, and 3 patients died during follow-up admissions (4 months-4 years later). There were 3 instances of hemorrhage related to liver biopsy. One patient underwent transplantation but died. Hematologic and biochemical markers did not discriminate well between survivors and nonsurvivors. The incidence of a second hepatic pathology (ie, viral hepatitis, autoimmune disease, transfusional siderosis) was 37% and was associated with the finding of more advanced histologic fibrosis. CONCLUSIONS: Patterns of hepatic dysfunction in sickle cell disease are diverse and demand clear characterization for each individual; however, groups with a poor prognosis can be identified after collation of clinical, laboratory, and radiologic data. Findings at biopsy (which is associated with higher risk of bleeding in this group) might be anticipated by noninvasive test results.

Proton pump inhibitors suppress absorption of dietary non-haem iron in hereditary haemochromatosis.

BACKGROUND AND AIMS: During the long-term treatment of patients with hereditary haemochromatosis (HH) the authors observed that proton pump inhibitors (PPI) reduced the requirement for maintenance phlebotomy. Gastric acid plays a crucial role in non-haem iron absorption and the authors performed a case review and intervention study to investigate if PPI-induced suppression of gastric acid would reduce dietary iron absorption in C282Y homozygous patients. METHODS: Phlebotomy requirements to keep serum ferritin approximately 50 microg/l before (mean 6.1 (SE 0.6) years) and during (3.8 (0.9) years) administration of a PPI were evaluated in seven patients and a post-prandial study was performed to determine whether PPIs reduce absorption of non-haem iron (14.5 mg) from a test meal in a further 14 phlebotomised patients with normal iron stores. RESULTS: There was a significant reduction (p<0.001) in the volume of blood removed annually before (2.5 (0.25) l) and while taking (0.5 (0.25) l) a PPI. Administration of a PPI for 7d suppressed absorption of non-haem iron from the meal as shown by a significant reduction (all p<0.01) in: area under the serum curve (2145 (374) versus 1059 (219)), % recovery of administered iron at peak serum iron (20.5 (3.2) versus 11.0 (2.0)%) and peak serum iron (13.6 (2.4) vs 6.1 (1.2) micromol/l) (all values are before vs during PPI). CONCLUSIONS: Administration of a PPI to patients with HH can inhibit the absorption of non-haem iron from a test meal and the habitual diet.

Antioxidants versus corticosteroids in the treatment of severe alcoholic hepatitis--a randomised clinical trial.

BACKGROUND/AIMS: Severe alcoholic hepatitis is associated with high morbidity and short-term mortality. Corticosteroids are the only widely used therapy but established contraindications to treatment or the risk of serious side-effects limit their use. The perceived need for alternative treatments together with the theoretical benefits of anti-oxidant therapy triggered the design of a randomised clinical trial comparing these treatment modalities. METHODS: One hundred and one patients were randomized into a clinical trial of corticosteroids or a novel antioxidant cocktail with a primary endpoint of 30-day mortality. RESULTS: At 30 days there were 16 deaths (30%) in the corticosteroid treated group compared with 22 deaths (46%) in the antioxidant treated group (P=0.05). The odds of dying by 30 days were 2.4 greater for patients on antioxidants (95% confidence interval 1.0-5.6). A diagnosis of sepsis was made more frequently in the AO group (P=0.05), although microbiologically proven episodes of infection occurred more often in the CS group (P<0.01). The survival advantage for corticosteroid treated patients was lost at 1 year of follow-up (P=0.43). CONCLUSIONS: This study has shown that corticosteroids in the form of prednisolone 30 mg daily are superior to a broad antioxidant cocktail in the treatment of severe alcoholic hepatitis.