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11- Systemic Hypertension

european anabolic systems mt10

The following drugs have a direct effect on bile secretory mechanisms: Addition of the nucleoside analog ribavirin, — mg daily in two divided doses, results in higher sustained response rates than interferon or peginterferon alone in previously untreated patients with chronic hepatitis C or patients who have had a relapse after an initial response to interferon alfa alone. Six participants with early stage dementia completed the intervention that was co-delivered by lay and clinical professional tutors.


A decrease in the expression of hepcidin, the principal iron regulatory hormone, is also thought to lead to increased ferroportin-1 expression. Once the serum nonceruloplasmin copper level is within the normal range, the dose of chelating agent can be reduced to the minimum necessary for maintaining that level. Google Fiber is part of the Access division of Alphabet Inc. A fully automated electrochemiluminescence assay from Roche Diagnostics and an HPLC based method from Chromsystems were used to measure vitamin D levels in surplus sera from 96 individuals, where the majority has the D2 form of the vitamin. Adsorption isotherms conformed to both the Langmuir and Freundlich equations and adsorption capacities were greater for beached pellets than for virgin pellets. For patients with fulminant hepatic failure of other causes, the outlook is especially poor in patients younger than 10 and older than 40 years of age and in those with an idiosyncratic drug reaction. Using analyses stratified by life history stage, we demonstrate a pattern of tolerance to macroparasites in mature compared to immature males.

Although, the endocrine actions of vitamin D are thoroughly appreciated, the effect of vitamin D on bone tissue and bone cells is yet to be completely understood. There exists a wealth of literature that suggests the VDR within the three major bone cell types, osteoblasts, osteocytes and osteoclasts, is responsible for the regulation of bone homeostasis. The circumstances, under which the action of 1,dihydroxyvitamin D3 elicits an anabolic or catabolic role have not been elucidated.

However, it would seem that vitamin D can evoke both of these effects and that this is partly mediated by calcium homeostasis. This raises the possibility that dietary calcium intake and vitamin D metabolism act concomitantly at the kidney, intestine and the bone in a coordinated response.

Thus, to maintain adequate bone homeostasis and reduce the risk of metabolic bone disease via the diet, it is important to consider this duality of vitamin D action in relation to the overall calcium economy.

Vitamin D activities and metabolic bone disease. Vitamin D activity requires an adequate vitamin D status as indicated by the serum level of hydroxyvitamin D and appropriate expression of genes coding for vitamin D receptor and hydroxyvitamin D 1? Vitamin D deficiency contributes to the aetiology of osteomalacia and osteoporosis.

The key element of osteomalacia, or rickets in children, is a delay in mineralization. It can be resolved by normalisation of plasma calcium and phosphate homeostasis independently of vitamin D activity. The well characterised endocrine pathway of vitamin D metabolism generates plasma 1,dihydroxyvitamin D and these endocrine activities are solely responsible for vitamin D regulating plasma calcium and phosphate homeostasis and protection against osteomalacia.

In contrast, a large body of clinical data indicate that an adequate serum hydroxyvitamin D level improves bone mineral density protecting against osteoporosis and reducing fracture risk. Recent research demonstrates that the three major bone cell types have the capability to metabolise hydroxyvitamin D to 1,dihydroxyvitamin D to activate the vitamin D receptor and modulate gene expression. Dietary calcium intake interacts with vitamin D metabolism at both the renal and bone tissue levels to direct either a catabolic action on bone through the endocrine system when calcium intake is inadequate or an anabolic action through a bone autocrine or paracrine system when calcium intake is sufficient.

A feasibility study into the production of a freeze-dried oyster reference material for paralytic shellfish poisoning toxins. Matrix reference materials are an essential component for the validation and quality control of analytical methodologies for the quantitation of marine biotoxins in shellfish.

Given the potential advantages of reference materials in powder form, a study was conducted to assess the feasibility for the production of a freeze-dried oyster tissue reference material containing a range of important paralytic shellfish poisoning toxins. One bulk sample of a wet oyster tissue homogenate was generated following mass culturing of toxic Alexandrium and oyster feeding experiments.

The bulk tissue was used to prepare untreated wet frozen aliquots with the remainder being freeze-dried and processed into appropriately-sized powder samples. A pre-column oxidation LC-FLD analysis was used to confirm the absence of any chromatographic artefacts resulting from the processing and to confirm acceptable homogeneity of the tissues.

Excellent stability over both the short-term 1 month and long-term 1 year of the freeze-dried material was demonstrated as compared with the stability of the untreated wet tissue. A post-column oxidation LC-FLD method was used to confirm the absence of toxin epimerisation in freeze-dried tissues which were observed in the wet tissues. Overall the work showed the feasibility of an approach to produce a homogenous freeze-dried oyster matrix material with enhanced stability in comparison to the untreated wet tissue.

The potential for use of the process for preparation of large scale production batches of a freeze-dried CRM for paralytic shellfish poisoning toxins has therefore been demonstrated. Development and qualitative evaluation of a self-management workshop for testicular cancer survivor-initiated follow-up. To describe the needs of testicular cancer survivors, develop a nurse-led workshop, and explore the experience of participation.

Distributions and concentrations of thallium in surface waters of a region impacted by historical metal mining Cornwall, UK. Kristi Tatsi , Andrew Turner. Thallium is a highly toxic heavy metal whose concentrations and distributions in the aquatic environment are poorly defined. In this study, concentrations of aqueous and total Tl have been measured in water samples from a variety of rivers and effluents the latter related to historical metal mining in the county of Cornwall, SW England.

Aqueous concentrations ranged from about 13ngL -1 in a river whose catchment contained no metal mines to ngL -1 in water abstracted directly from an abandoned mine shaft. Concentrations of Tl in rivers were greatest in the vicinity of mine-related effluents, with a maximum value measured of about ngL Thallium was not efficiently removed by the conventional, active treatment of mine water, and displayed little interaction with suspended particles.

Its mobility in surface waters, coupled with concentrations that are close to a quality guideline of ngL -1 , is cause for concern.

Accordingly, we recommend that the metal is more closely monitored in this and other regions impacted by mining activities. Extra- and intra-cellular accumulation of platinum group elements by the marine microalga, Chlorella stigmatophora.

In short-term exposures, and under all conditions, the extent of accumulation by C. Accumulation isotherms were quasi-linear up to added PGE concentrations of 30?

In the longer-term exposure, kinetic constraints on the reactivities of Rh and, in particular, Pt, resulted in final degrees of accumulation and internalisation by C. Among the PGE, therefore, Rh is predicted to participate in biological removal and transport processes in the marine environment to the greatest extent while decoupling in the biogeochemistries of Pd and Pt is predicted in shorter-term or more transient processes.

Neonatal herpes simplex 2 infection presenting with supraglottitis. We describe an unusual case of neonatal HSV-2 infection presenting with supraglottitis. Despite a 2 month course of intravenous aciclovir followed by 2 months of oral valaciclovir, the infant subsequently developed HSV-2 encephalitis which responded to further antiviral treatment. The subsequent diagnosis of encephalitis highlights the importance of testing CSF for HSV to establish the presence of CNS infection in neonates and thus the potential benefit of longer term suppressive antiviral therapy.

Concentrations and bioaccessibilities of trace elements in barbecue charcoals. Annabel Sharp , Andrew Turner. Total concentrations available to boiling aqua regia were greater in briquetted products with mean concentrations ranging from 0. On ashing, and with the exception of Hg, elemental concentrations increased by factors ranging from about 1.

Concentrations in the ashed products that were bioaccessible, or available to a physiologically based extraction test PBET that simulates, successively, the chemical conditions in the human stomach and intestine, exhibited considerable variation among the elements studied.

Feasibility studies into the production of gamma-irradiated oyster tissue reference materials for paralytic shellfish poisoning toxins.

A study was conducted to assess the feasibility for the production of sterile, stable and homogenous shellfish reference materials containing known concentrations of paralytic shellfish poisoning PSP toxins. Pacific oysters were contaminated with toxins following mass culturing of toxic algae and shellfish feeding experiments. Live oysters were shucked and tissues homogenised, before measuring into multiple aliquots, with one batch subjected to gamma irradiation treatment and the other remaining untreated.

The homogeneity of both batches of samples was assessed using a pre-column oxidation liquid chromatography with fluorescence detection Pre-COX LC-FLD method and shown to be within the limits of normal within-batch repeatability. This issue was not present in the tissues irradiated before long term storage.

Biological activity testing confirmed the absence of bacteria in the irradiated samples throughout the 12 month study period. With such results there was clear evidence for the potential of increasing the scale of the mass culturing and shellfish feeding for the production of large batches of tissue suitable for the preparation of a certified matrix reference material.

Oxidative DNA damage may not mediate Ni-induced genotoxicity in marine mussels: Nickel Ni is a known carcinogenic and mutagenic compound and an important contaminant of aquatic environments. Ni toxicity and its potential impact on aquatic organisms are, however, not well understood. This study used an integrated approach to evaluate genotoxic effects, tissue-specific accumulation and transcriptional profiles of key genes in mussels, Mytilus galloprovincialis, exposed to a range of concentrations of Ni.

Six genes pgp, mt10, mt20, sod, hsp70 and gst were selected for transcriptional analysis in the gills based on their key role in the stress response. Following exposure to sublethal concentrations of Ni ?

There was no significant difference between buffer control and enzyme treatments which target oxidised DNA bases formamidopyrimidine glycosylase or endonuclease IIII. This suggested that, in haemocytes, oxidative DNA damage is not a major mechanism for Ni-induced genotoxicity.

The expression of mt20 and gst genes in gill was up-regulated at genotoxic concentrations, whilst pgp expression was markedly up-regulated, particularly at 18? What are the most effective techniques in changing obese individuals physical activity self-efficacy and behaviour: Increasing self-efficacy is generally considered to be an important mediator of the effects of physical activity interventions. A previous review identified which behaviour change techniques BCTs were associated with increases in self-efficacy and physical activity for healthy non-obese adults.

The aim of the current review was to identify which BCTs increase the self-efficacy and physical activity behaviour of obese adults. A systematic search identified 61 comparisons with obese adults reporting changes in self-efficacy towards engaging in physical activity following interventions.

Of those comparisons, 42 also reported changes in physical activity behaviour. Meta-analysis was conducted with moderator analyses to examine the association between whether or not each BCT was included in interventions, and size of changes in both self-efficacy and physical activity behaviour. Overall, a small effect of the interventions was found on self-efficacy d?

Selenium in sediments and biota from estuaries of southwest England. Selenium concentrations have been measured in sediment, fucoid macroalgae and macroinvertebrates from four estuaries of SW England Yealm, Plym, Looe, Fal. Sediment concentrations ranged from about 0. Concentrations in Fucus vesiculosus 0.

Although Se concentrations in some invertebrates exceed toxicity thresholds for the diet of predacious birds and fish, no specific evidence for Se toxicity exists in these estuaries. Biomonitoring of thallium availability in two estuaries of southwest England. Thallium is a highly toxic metal whose biogeochemical behaviour in the marine environment is poorly understood.

We measured Tl in sediments, macroalgae Fucus vesiculosus and Fucus ceranoides and deposit-feeding invertebrates Hediste diversicolor, Arenicola marina and Scrobicularia plana from two estuaries of south west England Plym and Fal draining mineralised catchments.

In the Plym, and for a given sample type, concentrations of Tl were rather invariant between sample locations and averaged about ? In the Fal, respective concentrations were of a similar order of magnitude but exhibited greater variation between sample locations.

Despite the low bioaccumulation of Tl relative to other metals measured concurrently, it is recommended that Tl be more closely monitored and better studied in the estuarine environment. Do interventions to promote walking in groups increase physical activity?

Walking groups are increasingly being set up but little is known about their efficacy in promoting physical activity. The present study aims to assess the efficacy of interventions to promote walking in groups to promoting physical activity within adults, and to explore potential moderators of this efficacy. A simplified method for determining titanium from TiO2 nanoparticles in fish tissue with a concomitant multi-element analysis.

The reliable detection of nanoparticles NPs in fish tissue is required to support ecotoxicological research and food safety investigations.

Therefore the current work aimed to develop a simple method to determine Ti from TiO2 NPs in fish tissue whilst simultaneously measuring other elements in the sample. Spike recovery tests showed no differences when digestion was conducted in glass or plastic vials, there was stirring or sonication of the samples, or when sodium dodecyl sulfate was added.

Transformation of paralytic shellfish poisoning toxins in UK surf clams Spisula solida for targeted production of reference materials.

The periodic occurrence of Paralytic Shellfish Poisoning PSP toxins in UK surf clams and the recent move away from biological assays for PSP testing resulted in the need to determine method performance characteristics for the replacement analytical method in this species. With the requirement for laboratory reference materials to aid this validation together with known issues relating to toxin transformation in live clams and homogenised tissue, there was the need to assess the toxin transformation characteristics of PSP toxins in surf clam tissue.

Initial work examined the rates of toxin transformation in UK surf clam tissue incubated with toxin standards, showing rapid transformation of N-sulfocarbamoyl toxins with slower transformation of carbamate toxins. Full transformational pathways were determined using a combination of three different analytical methods and confirmed the major expected transformations involving decarbamoylation, with some evidence for additional reaction pathways.

Results obtained from the analysis of surf clam and oyster tissues incubated with varying concentrations of toxic Alexandrium algae highlighted expected transformation reactions, although significant differences were observed in the extent of the transformations amongst the range of toxins studied, with less efficient transformation of N-hydroxylated toxins as compared with other carbamate and N-sulfocarbamoyl toxins.

Analysis of PSP-toxic incurred oyster, scallop and mussel tissues incubated with variable proportions of surf clam tissue showed large differences in the extent of the transformations. Total conversion of N-sulfocarbamoyl toxins was confirmed at low relative proportions of surf clam tissue in all three species, whereas transformation of carbamate toxins was found to occur only in the presence of higher proportions of surf clam tissue in oysters and mussels in comparison with scallops.

Results enabled the production of three laboratory reference materials prepared following incubation of incurred homogenates with optimum proportions of surf clam tissue, resulting in materials containing a large number of PSP toxins.

Stability experiments provided good preliminary evidence for the stability of these targeted materials under storage conditions. The work therefore provides both additional information relating to the transformational activity in UK surf clams and highlights a good potential method for the targeted production of reference materials which include a wider range of toxins than normally present in naturally incurred shellfish. This study compared two methods of assaying the hydroxylated metabolites of cholecalciferol vitamin D3 and ergocalciferol vitamin D2.

A fully automated electrochemiluminescence assay from Roche Diagnostics and an HPLC based method from Chromsystems were used to measure vitamin D levels in surplus sera from 96 individuals, where the majority has the D2 form of the vitamin. Deming regression, concordance rate, correlation and Altman Bland agreement were performed.

Overall, the Roche Diagnostics method showed a negative bias of The overall correlation had an r value of 0. The observed bias had little impact on clinical decision and therefore is clinically acceptable. Wild rodents as a model to discover genes and pathways underlying natural variation in infectious disease susceptibility. Andrew K Turner , Steve Paterson. Individuals vary in their susceptibility to infectious disease and it is now well established that host genetic factors form a major component of this variation.

The discovery of genes underlying susceptibility has the potential to lead to improved disease control, through the identification and management of vulnerable individuals and the discovery of novel therapeutic targets. Laboratory rodents have proved invaluable for ascertaining the function of genes involved in immunity to infection. However, these captive animals experience conditions very different to the natural environment, lacking the genetic diversity and environmental pressures characteristic of natural populations, including those of humans.

It has therefore often proved difficult to translate basic laboratory research to the real world. In order to further our understanding of the genetic basis of infectious disease resistance, and the evolutionary forces that drive variation in susceptibility, we propose that genetic research traditionally conducted on laboratory animals is expanded to the more ecologically valid arena of natural populations.

In this article we highlight the potential of using wild rodents as a new resource for biomedical research, to link the functional genetic knowledge gained from laboratory rodents with the variation in infectious disease susceptibility observed in humans and other natural populations.

Investigations into matrix components affecting the performance of the official bioassay reference method for quantitation of paralytic shellfish poisoning toxins in oysters. Significant differences previously observed in the determination of paralytic shellfish poisoning toxins PSTs in oysters using official method AOAC In order to prove the cause of these large differences, work was conducted here to examine the presence and effects of matrix components on the performance of each of the two assays.

A range of oyster, cockle and mussel samples were extracted using the AOAC Firstly, a number of PSP-positive oyster samples were processed to reduce the concentrations of metals within the extracts, without significantly reducing the concentrations of PSTs. Secondly, a range of mussel and cockle extracts, plus a standard solution of saxitoxin di-hydrochloride were spiked at variable concentrations of zinc. Results proved the absence of any effect of metals on the performance of the LC-FLD, whilst showing a large suppressive effect of the metals on the MBA.

As such, the results show the performance of the official MBA is potentially unsafe for application to the routine monitoring of PSP toxicity in oysters or in any other shellfish found to contain high concentrations of metal ions. Interactions of silver nanoparticles with the marine macroalga, Ulva lactuca. Aqueous Ag was toxic at available concentrations as low as about 2. AgNP were not phytotoxic to the macroalga at available Ag concentrations up to at least 15?

At higher AgNP concentrations, a dose-response relationship was observed that was similar to that for aqueous Ag recorded at much lower concentrations. Persistence and metallic composition of paint particles in sediments from a tidal inlet. Concentrations of Cu, Pb, Sn and Zn have been determined in sediment ? Paint particles contributed up to about 0. Metal concentrations in the paint particles pooled from the sections were highly variable, typically spanning two orders of magnitude in each core, and were greatest for Cu and Zn up to , and ,?

Concentrations of metals in the sediment were, however, relatively invariant, an effect attributed to the abundance and dispersion of microscopic paint particles throughout the cores. Bioaccumulation of metals by Fucus ceranoides in estuaries of South West England. Fucus ceranoides tolerates abiotic conditions encountered across the full range of estuarine salinities.

We examined the bioaccumulation of metals in individuals and metal concentrations in accompanying sediment samples collected at different locations along estuaries of South West England. Intra- and inter-estuarine variations in metal accumulation by F.

Greatest accumulation was observed in estuaries that remain most heavily impacted by historical mining activities and for metals that were mobilised to the greatest extent during these operations As, Cu, Sn, Zn. Arsenic concentrations displayed a seaward increase in estuaries in which multiple samples were taken, whereas Cd concentrations were always greatest in samples collected from the most landward locations.

Ongoing research aims to better understand the mechanisms and kinetics of metal interactions with F. Adsorption of trace metals to plastic resin pellets in the marine environment. Plastic production pellets collected from beaches of south west England contain variable concentrations of trace metals Cr, Co, Ni, Cu, Zn, Cd and Pb that, in some cases, exceed concentrations reported for local estuarine sediments.

The rates and mechanisms by which metals associate with virgin and beached polyethylene pellets were studied by adding a cocktail of 5? Kinetic profiles were modelled using a pseudo-first-order equation and yielded response times of less than about h and equilibrium partition coefficients of up to about ml g -1 that were consistently higher for beached pellets than virgin pellets. Adsorption isotherms conformed to both the Langmuir and Freundlich equations and adsorption capacities were greater for beached pellets than for virgin pellets.

Results suggest that plastics may represent an important vehicle for the transport of metals in the marine environment. Concentrations and bioaccessibilities of metals in exterior urban paints. Paint fragments have been collected from a variety of structures e. Concentrations of most metals were highly variable and spanned several orders of magnitude among the samples e.

The bioaccessibilities of the metals were evaluated using a physiologically based extraction test that simulates the chemical conditions of the human stomach and intestine. The bioaccessibility of a given metal was highly variable among the samples and was greater in the stomach than the intestine in some cases e. Cd, Pb and greater in the intestine in others e.

Based on total and bioaccessible concentrations in urban paints, Pb remains the metal of greatest concern from a human health perspective. Thallium in the hydrosphere of south west England. Sin Law , Andrew Turner. Thallium is a highly toxic metal whose environmental concentrations, distributions and behaviour are not well understood.

In the present study we measure the concentrations of Tl in filtered and unfiltered samples of rain, tap, river, estuarine and waste waters collected from south west England. An evaluation of the toxicity and bioaccumulation of cisplatin in the marine environment using the macroalga, Ulva lactuca. The cytotoxic drug, cisplatin cis-PtCl 2 NH 3 2 , has been added to cultures of the marine macroalga, Ulva lactuca, under various experimental conditions. Despite its mode of action at the cellular level, cisplatin added up to concentrations of nM did not incur a measurable reduction in the efficiency of photochemical energy conversion under any of experimental conditions tested.

Trace metals in harbour and slipway sediments from the island of Malta, central Mediterranean. Emily J Huntingford , Andrew Turner. Leaching of zinc from tire wear particles under simulated estuarine conditions. Fanule S Degaffe , Andrew Turner. Tire wear particles TWP abraded from end-of-life passenger car tires have been added at a concentration of 1 g L?

Results of time-dependent experiments conducted over a period of 5 days were consistent with a diffusion controlled leaching mechanism with rate constants of about 0. Additional experiments revealed a reduction in Zn dissolution with both increasing salinity and pH and enhancement of leaching in the presence of fluorescent light compared with dark conditions.

In corresponding experiments conducted in the presence of a fixed quantity 0. Increasing the quantity of sediment resulted in a progressive reduction in Zn concentration until an apparent equilibrium was achieved, with partition coefficients defining the sediment-water distribution of Zn of about mL g? The findings of the study are discussed in terms of their implications for the transport, fate and effects of TWP Zn in aquatic environments that are likely to receive urban runoff. Genetic diversity in cytokines associated with immune variation and resistance to multiple pathogens in a natural rodent population.

Pathogens are believed to drive genetic diversity at host loci involved in immunity to infectious disease. To date, studies exploring the genetic basis of pathogen resistance in the wild have focussed almost exclusively on genes of the Major Histocompatibility Complex MHC ; the role of genetic variation elsewhere in the genome as a basis for variation in pathogen resistance has rarely been explored in natural populations.

Cytokines are signalling molecules with a role in many immunological and physiological processes. Here we use a natural population of field voles Microtus agrestis to examine how genetic diversity at a suite of cytokine and other immune loci impacts the immune response phenotype and resistance to several endemic pathogen species.

By using linear models to first control for a range of non-genetic factors, we demonstrate strong effects of genetic variation at cytokine loci both on host immunological parameters and on resistance to multiple pathogens. These effects were primarily localized to three cytokine genes Interleukin 1 beta Il1b , Il2, and Il12b , rather than to other cytokines tested, or to membrane-bound, non-cytokine immune loci.

The observed genetic effects were as great as for other intrinsic factors such as sex and body weight. Our results demonstrate that genetic diversity at cytokine loci is a novel and important source of individual variation in immune function and pathogen resistance in natural populations. The products of these loci are therefore likely to affect interactions between pathogens and help determine survival and reproductive success in natural populations.

Our study also highlights the utility of wild rodents as a model of ecological immunology, to better understand the causes and consequences of variation in immune function in natural populations including humans. Sexual behavior and HPV infection in British women, by postal questionnaires and telephone interviews. Sexually transmitted human papillomaviruses HPVs , most frequently HPV 16, are the primary cause of cervical carcinogenesis. Questions on sexual history included age at first sexual intercourse, sexually transmitted diseases, lifetime total and regular sexual partners, and number of partners in the last 5 years total and new.

Demographics, reproductive, cervical screening, and smoking history were also collected in questionnaires. There was good agreement Odds ratios OR for both HPV prevalence and acquisition increased consistently with increasing numbers of lifetime sexual partners, regular partners, and new partners in the last 5 years recent partners.

No significant association was found for other characteristics investigated. Vitamin D metabolism within bone cells: The endocrine activity of 1,dihydroxyvitamin D 1,25 OH 2 D 3 contributes to maintaining plasma calcium and phosphate homeostasis through actions on the intestine, kidney and bone. Sustained response to intrathecal rituximab in EBV associated Post-transplant lymphoproliferative disease confined to the central nervous system following haematopoietic stem cell transplant.

These children had failed to respond to standard chemotherapy, intravenous rituximab and EBV specific cellular therapy. Cortical responses to a graded working memory challenge predict functional decline in mild cognitive impairment. Early detection of progressive cognitive decline offers an opportunity for preventative interventions with enormous public health implications. Functional neuroimaging during cognitive activity in individuals at risk of dementia has the potential to advance this objective.

In a prior study, we evaluated the utility of a novel functional magnetic resonance imaging paradigm that incorporated a graded working memory WM task to detect changes associated with mild cognitive impairment MCI. Our objective here is to test whether this paradigm can predict ensuing functional decline. Oral bioaccessibility of trace metals in household dust: Because household dust is a heterogeneous assortment of particles derived from a multitude of diverse sources, concentrations of toxicants, like trace metals, vary widely among sample populations.

For risk assessment purposes, the bioaccessibility of a trace metal, or its degree of solubilization in the human lung or digestive environment, provides a better metric of its potential health impact than its total concentration.

In this paper, the relatively little direct information that exists on the in vitro oral bioaccessibilities of metals in household dust is reviewed. Data and mechanisms from studies involving better characterized geosolids, like soil and street dust, or metal-rich components thereof, such as paints, are also extrapolated to the household setting, although use of these solids as surrogates of household dust is not recommended.

While part of this variation reflects the inherent heterogeneity of samples arising from local to regional differences in geology, industrial emissions, and domestic and cultural practices, considerable variation results from the precise means by which bioaccessibility is determined in vitro.

It is recommended, therefore, that the effects of physicochemical variables, and in particular, the solid to fluid ratio and the pH of the stomach phase, are studied systematically such that appropriate algorithms or corrections may be factored into measures of bioaccessibility obtained under operationally defined default conditions. Accumulation of platinum group elements by the marine gastropod Littorina littorea.

Rachel Mulholland , Andrew Turner. The accumulation and trophic transfer of the platinum group elements PGE: Metals added to sea water to concentrations of 20? Rh, with greatest metal accumulation in the latter generally occurring in the visceral complex and kidney.

When fed contaminated alga, accumulation of Rh and Pd by L. We conclude that the diet is the most important vector for accumulation of Rh and Pd, while accumulation of Pt appears to proceed mainly from the aqueous phase. The additional sensitivity of HPV testing compared with cytology could permit extended cervical screening intervals.

Leaching of Cu and Zn from discarded boat paint particles into tap water and rain water. Adam Jessop , Andrew Turner. We studied the leaching of copper and zinc from particles of discarded boat paint added to tap water pH 7. Leaching rates appeared to be diffusion-controlled and were greater in rain water than in tap water and were greater for Zn than for Cu.

After a period of h, between about 0. These observations suggest that Cu and Zn mobilised from fine antifouling particulates during washdown or rainfall events may be important contaminants of runoff and soils in the vicinity of boat repair facilities.

A single-laboratory validation study of this method was undertaken here for the analysis of PSP toxins in oysters, cockles, clams, and razor clams. Alcoholic hepatitis may be closely mimicked by cholecystitis and cholelithiasis and by drug toxicity.

Other causes of hepatitis or chronic liver disease may be excluded by serologic or biochemical testing, by imaging studies, or by liver biopsy.

Abstinence from alcohol is essential. Fatty liver is quickly reversible with abstinence. Every effort should P. Failure of the serum bilirubin level to decline after 7 days of treatment predicts nonresponse and poor long-term survival. No benefit has been demonstrated in patients with concomitant gastrointestinal bleeding.

Pentoxifylline an inhibitor of tumor necrosis factor mg orally three times daily for 4 weeks, may reduce 1-month mortality rates in patients with severe alcoholic hepatitis, primarily by decreasing the risk of hepatorenal syndrome. Other experimental therapies include propylthiouracil, oxandrolone, S -adenosyl-L-methionine, infliximab, and extracorporeal liver support. Colchicine has been shown not to reduce mortality in patients with alcoholic cirrhosis.

In addition to the discriminant function discussed above, the Model for End-Stage Liver Disease MELD score used for cirrhosis see later correlates with mortality from alcoholic hepatitis. In the United States, the 3-year mortality rate of persons who recover from acute alcoholic hepatitis is ten times greater than that of control individuals of comparable age.

Histologically severe disease is associated with continued excessive mortality rates after 3 years, whereas the death rate is not increased after the same period in those whose liver biopsies show only mild alcoholic hepatitis. Complications of portal hypertension ascites, variceal bleeding, hepatorenal syndrome , coagulopathy, and severe jaundice following recovery from acute alcoholic hepatitis also suggest a poor long-term prognosis. The most important prognostic consideration is continued excessive drinking.

A 6-month period of abstinence is generally required before liver transplantation is considered, although this requirement has been questioned.

Dunn W et al: MELD accurately predicts mortality in patients with alcoholic hepatitis. Forrest EH et al: Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score.

Corticosteroids for alcoholic hepatitis what's next? Morgan TR et al: Colchicine treatment of alcoholic cirrhosis: Srikureja W et al: Drug-induced liver disease can mimic viral hepatitis, biliary tract obstruction, or other types of liver disease. Clinicians must inquire about the use of many widely used therapeutic agents, including over-the-counter natural and herbal products, in any patient with liver disease.

The continuing synthesis, testing, and introduction of new drugs into clinical practice has resulted in an increase in toxic reactions of many types. Many widely used therapeutic agents, including over-the-counter natural and herbal products, may cause hepatic injury. The liver lesion caused by this group of drugs is characterized by 1 dose-related severity, 2 a latent period following exposure, and 3 susceptibility in all individuals.

Examples include acetaminophen toxicity is enhanced by fasting and chronic alcohol use because of depletion of glutathione and induction of cytochrome P 2E1 , alcohol, carbon tetrachloride, chloroform, heavy metals, mercaptopurine, niacin, plant alkaloids, phosphorus, tetracyclines, valproic acid, and vitamin A. Statins, like all cholesterol-lowering agents, may cause serum aminotransferase elevations but rarely, if ever, cause true hepatotoxicity.

Except for acetaminophen, most severe hepatotoxicity is idiosyncratic. Reactions of this type are 1 sporadic, 2 not related to dose, and 3 occasionally associated with features suggesting an allergic reaction, such as fever and eosinophilia. In some, toxicity results directly from a metabolite that is produced only in certain individuals on a genetic basis. Examples include amiodarone, aspirin, carbamazepine, chloramphenicol, diclofenac, flutamide, halothane, isoniazid, ketoconazole, lamotrigine, methyldopa, oxacillin, phenytoin, pyrazinamide, quinidine, streptomycin, rofecoxib and troglitazone both withdrawn from the market in the United States , and less commonly other thiazolidinediones, and perhaps tacrine.

The following drugs have a direct effect on bile secretory mechanisms: The following drugs cause inflammation of portal areas with bile duct injury cholangitis , often with allergic features such as eosinophilia: Acute or Chronic Hepatitis.

Medications that may result in acute or chronic hepatitis that is histologically and in some cases clinically indistinguishable from autoimmune hepatitis include aspirin, isoniazid increased risk in HBV carriers , methyldopa, minocycline, nitrofurantoin, nonsteroidal anti-inflammatory drugs, and propylthiouracil.

Hepatitis also can occur in patients taking cocaine, ecstasy, efavirenz, nevirapine increased risk in HBV and HCV carriers , ritonavir greater rate than other protease inhibitors , sulfonamides, troglitazone withdrawn from the market in the United States , and zafirlukast as well as a variety of alternative remedies eg, chaparral, germander, jin bu huan, skullcap, kava.

Microvesicular often resulting from mitochondrial injury. Sinusoidal Obstruction Syndrome Veno-occlusive Disease. Peliosis Hepatis Blood-Filled Cavities.

Oral contraceptive steroids, estrogens hepatic adenoma but not focal nodular hyperplasia ; vinyl chloride angiosarcoma. Bj rnsson E et al: Outcome and prognostic markers in severe drug-induced liver disease. Charles EC et al: Evaluation of cases of severe statin-related transaminitis within a large health maintenance organization. Navarro VJ et al: Rostom A et al: Nonsteroidal anti-inflammatory drugs and hepatic toxicity: Stickel F et al: Ethanol can cause hepatic steatosis fatty liver in the absence of malnutrition, although inadequate diets specifically those deficient in choline, methionine, and protein can contribute to liver damage caused by ethanol see earlier.

Steatosis is nearly universal in obese alcoholic patients and is a hallmark of insulin resistance syndrome, which is characterized by obesity, diabetes, hypertriglyceridemia, and hypertension. The risk of fatty liver in persons with insulin resistance syndrome is 4 to 11 times higher than that of persons without insulin resistance. In addition to macrovesicular steatosis, histologic features may include focal infiltration by polymorphonuclear neutrophils and Mallory's hyalin, a picture indistinguishable from that of alcoholic hepatitis and referred to as nonalcoholic steatohepatitis NASH.

In patients with NAFLD, older age, obesity, and diabetes are risk factors for advanced hepatic fibrosis and cirrhosis. Microvesicular steatosis is seen with Reye's syndrome, valproic acid toxicity, high-dose tetracycline, or acute fatty liver of pregnancy and may result in fulminant hepatic failure.

Women in whom fatty liver of pregnancy develops often have a defect in fatty acid oxidation due to reduced long-chain 3-hydroxyacyl-CoA dehydrogenase activity. The exact stimulus that causes progression of steatosis to steatohepatitis and fibrosis second hit is unclear.

The leading possibility is lipid peroxidation and oxidative stress. Some patients with NAFLD have hepatic iron overload, and some of these patients are heterozygous for the CY gene for hemochromatosis HFE ; increased hepatic iron as well as severe steatosis both attributed to insulin resistance have been associated with hepatic fibrosis in some studies.

Most patients are asymptomatic or have mild right upper quadrant discomfort. Rare instances of subacute liver failure caused by previously unrecognized NASH have been described. Antinuclear or smooth muscle antibodies may be detected in one-fourth of patients with nonalcoholic steatohepatitis.

However, imaging does not distinguish steatosis from steatohepatitis. Percutaneous liver biopsy is diagnostic and is the only way to assess the degree of inflammation and fibrosis. The risks of the procedure must be balanced against the impact of the added information on management decisions and assessment of prognosis.

The histologic spectrum includes fatty liver, isolated portal fibrosis, nonalcoholic steatohepatitis, and cirrhosis. Treatment consists of removing or modifying the offending factors. Weight loss, dietary fat restriction, and exercise often lead to improvement in liver tests and steatosis in obese patients with fatty liver, but the benefit of such measures is less clear in patients with steatohepatitis.

Vitamin E to reduce oxidative stress is of uncertain benefit. Betaine a methyl donor may have some benefit and is under study. Metformin has been shown to reduce insulin resistance and reverse P. Fatty liver is readily reversible with discontinuation of alcohol or treatment of other underlying conditions. Otherwise, the course is variable. The course may be more aggressive in diabetic persons than in nondiabetic persons. Mortality is increased in patients with NAFLD and is more likely to be the result of malignancy and ischemic heart disease than liver disease.

Risk factors for mortality are older age, diabetes, and cirrhosis. Steatosis is a cofactor for the progression of fibrosis in patients with other causes of chronic liver disease, such as hepatitis C. Instances of hepatocellular carcinoma in patients with cirrhosis caused by NASH have been reported. NASH accounts for a substantial percentage of cases labeled as cryptogenic cirrhosis and can recur following liver transplantation. Central obesity is an independent risk factor for death from cirrhosis.

Adams LA et al: The natural history of nonalcoholic fatty liver disease: Bugianesi E et al: Fartoux L et al: Insulin resistance is a cause of steatosis and fibrosis progression in chronic hepatitis C. Hamaguchi M et al: The metabolic syndrome as a predictor of nonalcoholic fatty liver disease.

Kunde SS et al: Nonalcoholic fatty liver disease: Dig Dis Sci ; The clinical features result from hepatic cell dysfunction, portosystemic shunting, and portal hypertension. Cirrhosis is the end result of hepatocellular injury that leads to both fibrosis and nodular regeneration throughout the liver. Cirrhosis is a serious and generally irreversible disease and is the tenth leading cause of death in the United States.

In patients at increased risk of liver injury eg, heavy alcohol use, obesity, iron overload , higher coffee and tea consumption has been reported to reduce the risk of chronic liver disease. The clinical features of cirrhosis result from hepatic cell dysfunction, portosystemic shunting, and portal hypertension.

The most common histologic classification divides cirrhosis into micronodular, macronodular, and mixed forms. These are descriptive terms rather than separate diseases, and each form may be seen in the same patient at different stages of the disease. In micronodular cirrhosis typical of alcoholic liver disease Laennec's cirrhosis the regenerating nodules are no larger than the original lobules, ie, approximately 1 mm in diameter or less. Macronodular cirrhosis is characterized by larger nodules, which can measure several centimeters in diameter and may contain central veins.

This form corresponds more or less to postnecrotic posthepatitic cirrhosis but does not necessarily follow episodes of massive necrosis and stromal collapse. Cirrhosis may cause no symptoms for long periods. The onset of symptoms may be insidious or, less often, abrupt. Weakness, fatigability, disturbed sleep, muscle cramps, and weight loss are common. In advanced cirrhosis, anorexia is usually present and may be extreme, with associated nausea and occasional vomiting.

Abdominal pain may be present and is related either to hepatic enlargement and stretching of Glisson's capsule or to the presence of ascites.

Menstrual abnormalities usually amenorrhea , impotence, loss of libido, sterility, and gynecomastia in men may occur. Skin manifestations consist of spider nevi invariably on the upper half of the body , palmar erythema mottled redness of the thenar and hypothenar eminences , and Dupuytren's contractures.

Evidence of vitamin deficiencies glossitis and cheilosis is common. Weight loss, wasting, and the appearance of chronic illness are present. Jaundice usually not an initial sign is mild at first, increasing in severity during the later stages of the disease. Ascites, pleural effusions, peripheral edema, and ecchymotic lesions are late findings.

Encephalopathy characterized by day night reversal, asterixis, tremor, dysarthria, delirium, drowsiness, and ultimately coma also occur late except when precipitated by an acute hepatocellular insult or an episode of gastrointestinal bleeding. The superficial veins of the abdomen and thorax are dilated, reflecting the intrahepatic obstruction to portal blood flow, as do rectal varices.

The veins fill from below when compressed. Laboratory abnormalities are either absent or minimal in latent or quiescent cirrhosis. Anemia, a frequent finding, is often macrocytic; causes include suppression of erythropoiesis by alcohol as well as folate deficiency, hemolysis, hypersplenism, and insidious or overt blood loss from the gastrointestinal tract.

The white blood cell count may be low, reflecting hypersplenism, or high, suggesting infection; thrombocytopenia is secondary to alcoholic marrow suppression, sepsis, folate deficiency, or splenic sequestration. Prolongation of the prothrombin time may result from failure of hepatic synthesis of clotting factors. Blood chemistries reflect hepatocellular injury and dysfunction, manifested by modest elevations of AST and alkaline phosphatase and progressive elevation of the bilirubin.

Serum albumin is low; -globulin is increased and may be as high as in autoimmune hepatitis. The risk of diabetes mellitus is increased in patients with cirrhosis, particularly when associated with HCV infection, alcoholism, hemochromatosis, and NAFLD.

Patients with alcoholic cirrhosis may have elevated serum cardiac troponin I and brain natriuretic peptide levels. Blunted cardiac inotropic and chronotropic responses to exercise, stress, and drugs, as well as reduced ventricular function and prolongation of the QT interval, are common in cirrhosis of all causes, but overt heart failure is rare in the absence of alcoholism.

Liver biopsy may show inactive cirrhosis fibrosis with regenerative nodules with no specific features to suggest the underlying cause. Alternatively, there may be additional features of alcoholic liver disease, chronic hepatitis, or other specific causes of cirrhosis. Combinations of routine blood tests eg, AST, platelet count and serum markers of hepatic fibrosis eg, hyaluronic acid, amino-terminal propeptide of type III collagen, tissue inhibitor of matrix metalloproteinase 1 are under study as alternatives to liver biopsy for the diagnosis or exclusion of cirrhosis.

Plain films of the abdomen are seldom helpful. Barium studies of the upper gastrointestinal tract may reveal the presence of esophageal or gastric varices, although endoscopy is more sensitive. Ultrasound is helpful for assessing liver size and detecting ascites or hepatic nodules, including small hepatocellular carcinomas. Together with Doppler studies, it may establish patency of the splenic, portal, and hepatic veins.

Nodules suspicious for malignancy may be biopsied under ultrasound or CT guidance. Esophagogastroduodenoscopy confirms the presence of varices and detects specific causes of bleeding in the esophagus, stomach, and proximal duodenum. Liver biopsy may be performed by laparoscopy or, in patients with coagulopathy and ascites, by a transjugular approach.

In selected cases, wedged hepatic vein pressure measurement may establish the presence and cause of portal hypertension. Determining the cause of cirrhosis is important prognostically and therapeutically. The most common causes of cirrhosis are chronic hepatitis C and B and alcohol. Mutations in the keratin 8 gene have been associated with some cases of cryptogenic cirrhosis.

In advanced cases, hemochromatosis may be associated with bronzing of the skin, arthritis, heart failure, and diabetes; however, most patients have no symptoms or signs. Other metabolic diseases that may lead to cirrhosis include Wilson's disease and 1 -antiprotease 1 -antitrypsin deficiency. Primary biliary cirrhosis occurs more frequently in women and is associated with pruritus, significant elevation of alkaline phosphatase, elevated immunoglobulin IgM and hypercholesterolemia, and antimitochondrial antibody.

Secondary biliary cirrhosis may result from chronic biliary obstruction due to a stone, stricture, or neoplasm and is not associated with antimitochondrial antibody.

Congestive heart failure and constrictive pericarditis may lead to hepatic fibrosis cardiac cirrhosis complicated by ascites and may be mistaken for other causes of cirrhosis. Upper gastrointestinal tract bleeding may occur from varices, portal hypertensive gastropathy, or gastroduodenal ulcer see Chapter Hemorrhage may be massive, resulting in fatal exsanguination or encephalopathy. Varices may also result from portal vein thrombosis. Liver failure may be precipitated by alcoholism, surgery, and infection.

The risk of carcinoma of the liver is increased in patients with cirrhosis. Hepatic Kupffer cell reticuloendothelial dysfunction and decreased opsonic activity lead to an increased risk of systemic infection. The most important principle of treatment is abstinence from alcohol. The benefit of using specialized supplements containing branched-chain amino acids to prevent or treat hepatic encephalopathy or delay progressive liver failure is uncertain.

Vitamin supplementation is desirable. Diagnostic paracentesis is indicated for new ascites. It is rarely associated with serious complications such as bleeding, infection, or bowel perforation even in patients with severe coagulopathy. An elevated ascitic adenosine deaminase level is suggestive of tuberculous peritonitis, but the sensitivity of the test is reduced in patients with portal hypertension. Occasionally, cirrhotic ascites is chylous rich in triglycerides ; other causes of chylous ascites are malignancy, tuberculosis, and recent abdominal surgery or trauma.

Ascites in patients with cirrhosis results from portal hypertension increased hydrostatic pressure ; hypoalbuminemia decreased oncotic pressure ; peripheral vasodilation, perhaps mediated by endotoxin-induced release of nitric oxide from splanchnic and systemic vasculature, with resulting increases in renin and angiotensin levels and sodium retention by the kidneys; impaired liver inactivation of aldosterone; and increased aldosterone secretion secondary to increased renin production.

Free water excretion is also impaired in cirrhosis, and hyponatremia may develop. In some patients, there is a rapid diminution of ascites on bed rest and dietary sodium restriction alone.

Treatment of severe hyponatremia with vasopressin receptor antagonists is under study. Spironolactone, generally in combination with furosemide, should be used in patients who do not respond to salt restriction. An initial trial of furosemide 80 mg intravenously demonstrating a rise in urine sodium to mmol in 8 hours may predict response to diuretic therapy. Monitoring for hyperkalemia is important. In patients who cannot tolerate spironolactone because of side effects, such as painful gynecomastia, amiloride another potassium-sparing diuretic may be used in a dose of 5 10 mg orally daily.

Diuresis is augmented by the addition of a loop diuretic such as furosemide. This potent diuretic, however, will maintain its effect even with a falling glomerular filtration rate, with resultant prerenal azotemia.

The goal of weight loss in the ascitic patient without associated peripheral edema should be no more than 1 1. In patients with massive ascites and respiratory compromise, ascites refractory to diuretics, or intolerable diuretic side effects, large-volume paracentesis 4 6 L is effective.

Large-volume paracentesis can be repeated daily until ascites is largely resolved and may decrease the need for hospitalization. If possible, diuretics should be continued in the hope of preventing recurrent ascites.

Transjugular intrahepatic portosystemic shunt TIPS. TIPS is an effective treatment of variceal bleeding refractory to standard therapy eg, endoscopic band ligation or sclerotherapy and has shown P. In the past, peritoneovenous shunts were advocated for use in patients with refractory ascites. These shunts may be effective but carry a considerable complication rate: TIPS is now preferred for refractory ascites. Spontaneous bacterial peritonitis is heralded by abdominal pain, increasing ascites, fever, and progressive encephalopathy in a patient with cirrhotic ascites; symptoms are typically mild.

Rapid diagnosis of bacterial peritonitis can be made with a high degree of accuracy with rapid reagent strips dipsticks that detect leukocyte esterase in ascitic fluid. Common isolates are Escherichia coli and pneumococci. Gram-positive cocci are the most common isolates in patients who have undergone invasive procedures such as central venous line placement. Ceftriaxone and amoxicillin-clavulanic acid are alternatives. Oral ofloxacin, mg twice daily, or a 2-day course of intravenous ciprofloxacin, mg twice daily, followed by oral ciprofloxacin, mg twice daily for 5 days, may be effective in selected patients.

Supplemental administration of intravenous albumin may reduce mortality. In survivors, the risk of recurrent peritonitis may be decreased by long-term norfloxacin, mg orally daily although in recurrence the causative organism is often resistant to quinolones. Oliguria, hyponatremia, and low urinary sodium are typical features.

Hepatorenal syndrome is diagnosed only when other causes of renal failure including prerenal azotemia and acute tubular necrosis have been excluded. Type I hepatorenal syndrome is characterized by doubling of the serum creatinine to a level greater than 2.

Type II hepatorenal syndrome is more slowly progressive and chronic. The cause is unknown, but the pathogenesis involves intense renal vasoconstriction, possibly because of impaired synthesis of renal vasodilators such as prostaglandin E 2 and decreased total renal blood flow; histologically, the kidneys are normal. An acute decrease in cardiac output is often the precipitating event. Treatment is often ineffective. Improvement may follow intravenous infusion of albumin in combination with one of the following: Hepatic encephalopathy is a state of disordered central nervous system function resulting from failure of the liver to detoxify noxious agents of gut origin because of hepatocellular dysfunction and portosystemic shunting.

The clinical spectrum ranges from day night reversal and mild intellectual impairment to coma. Patients with minimal hepatic encephalopathy have no recognizable clinical symptoms but demonstrate mild cognitive and psychomotor deficits and attention deficit on standardized tests.

The stages of overt encephalopathy are 1 mild confusion, 2 drowsiness, 3 stupor, and 4 coma. Ammonia is the most readily identified and measurable toxin but is not solely responsible for the disturbed mental status. Pathogenic factors may include production of false neurotransmitters, increased sensitivity of central nervous system neurons to the inhibitory neurotransmitter -aminobutyric acid GABA , an increase in circulating levels of endogenous benzodiazepines, decreased activity of urea-cycle enzymes due to zinc deficiency, decreased brain levels of myoinositol, deposition of manganese in the basal ganglia, and swelling of astrocytes in the brain.

Bleeding into the intestinal tract may significantly increase the amount of protein in the bowel and precipitate rapid development of encephalopathy. Other precipitants include constipation, alkalosis, and potassium deficiency induced by diuretics, opioids, hypnotics, and sedatives; medications containing ammonium or amino compounds; paracentesis with attendant hypovolemia; hepatic or systemic infection; and portosystemic shunts including TIPS.

The diagnosis is based primarily on detection of characteristic symptoms and signs, including asterixis. The role of neuroimaging studies eg, cerebral positron emissions tomography, magnetic resonance spectroscopy in the diagnosis of hepatic encephalopathy is evolving. Dietary protein should be withheld during acute episodes if the patient cannot eat. Gastrointestinal bleeding should be controlled and blood purged from the gastrointestinal tract.

This can be accomplished with mL of magnesium citrate by mouth or nasogastric tube every 3 4 hours until the stool is free of gross blood, or by administration of lactulose. The value of treating patients with minimal hepatic encephalopathy is uncertain. Lactulose, a nonabsorbable synthetic disaccharide syrup, is digested by bacteria in the colon to short-chain fatty acids, resulting in acidification of colon contents.

Lactulose also leads to a change in bowel flora so that fewer ammonia-forming organisms are present. When given orally, the initial dose of lactulose for acute hepatic encephalopathy is 30 mL three or four times daily. The dose should then be titrated so that two or three soft stools per day are produced. When rectal use is indicated because of the patient's inability to take medicines orally, the dose is mL of lactulose in mL of saline or sorbitol as a retention enema for 30 60 minutes; it may be repeated every 4 6 hours.

Lactilol is a less sweet disaccharide alternative available as a powder in some countries. The ammonia-producing intestinal flora may also be controlled with neomycin sulfate, 0. Side effects of neomycin include diarrhea, malabsorption, superinfection, ototoxicity, and nephrotoxicity, usually only after prolonged use.

Alternative antibiotics are rifaximin mg orally daily, vancomycin, 1 g orally twice daily, or metronidazole, mg orally three times daily. Patients who do not respond to lactulose alone may improve with a 1-week course of an antibiotic in addition to lactulose. Opioids and sedatives metabolized or excreted by the liver are avoided.

If agitation is marked, oxazepam, 10 30 mg, which is not metabolized by the liver, may be given cautiously by mouth or by nasogastric tube. Eradication of Helicobacter pylori , which generates ammonia in the stomach, does not appear to improve encephalopathy. Sodium benzoate, 10 g orally daily, and ornithine aspartate, 9 g orally three times daily, may lower blood ammonia levels, but there is less experience with these drugs than with lactulose.

Use of special dietary supplements enriched with branched-chain amino acids is usually unnecessary except in occasional patients who are intolerant of standard protein supplements. Treatment by modulating the gut flora with prebiotic and probiotic agents is under study.

For iron deficiency anemia, ferrous sulfate, 0. Transfusions with packed red blood cells may be necessary to replace blood loss. Severe hypoprothrombinemia may be treated with vitamin K eg, phytonadione, 5 mg orally or subcutaneously daily. This treatment is ineffective when synthesis of coagulation P. Hemorrhage from esophageal varices. Shortness of breath in patients with cirrhosis may result from pulmonary restriction and atelectasis caused by massive ascites.

The syndrome is presumed to result from failure of the diseased liver to clear circulating pulmonary vasodilators. Patients often have dyspnea and arterial deoxygenation in the upright position orthodeoxia that is relieved by recumbency.

Contrast-enhanced echocardiography is a sensitive screening test for detecting pulmonary vascular dilations, whereas macroaggregated albumin lung perfusion scanning is more specific and is used to confirm the diagnosis. High-resolution CT may be useful for detecting dilated pulmonary vessels that may be amenable to embolization in patients who respond poorly to supplemental oxygen and is under study.

Medical therapy has been disappointing; however, intravenous methylene blue and oral garlic powder may improve oxygenation in patients by inhibiting nitric oxide-induced vasodilation. TIPS may provide palliation in patients with hepatopulmonary syndrome awaiting transplantation. Pulmonary hypertension occurs in 0. In some cases, treatment with epoprostenol or bosentan may reduce pulmonary hypertension and thereby facilitate liver transplantation; -blockers worsen exercise capacity and are contraindicated.

Liver transplantation is indicated in selected cases of irreversible, progressive chronic liver disease, acute hepatic failure, and certain metabolic diseases in which the metabolic defect is in the liver. Absolute contraindications include malignancy except small hepatocellular carcinomas in a cirrhotic liver , advanced cardiopulmonary disease except pulmonary arteriovenous shunting due to portal hypertension and cirrhosis , and sepsis.

Relative contraindications include age over 70 years, morbid obesity, portal and mesenteric vein thrombosis, active alcohol or drug abuse, HIV infection, severe malnutrition, and lack of patient understanding. With the emergence of effective antiretroviral therapy for HIV disease, a major cause of mortality in these patients has shifted to liver disease caused by HCV and HBV infection; preliminary experience suggests that the outcome of liver transplantation is comparable to that for non-HIV-infected liver transplant recipients.

Alcoholics should be abstinent for 6 months. Liver transplantation should be considered in patients with worsening functional status, rising bilirubin, decreasing albumin, worsening coagulopathy, refractory ascites, recurrent variceal bleeding, or worsening encephalopathy. The major impediment to more widespread use of liver transplantation is a shortage of donor organs. Increasingly, adult living donor liver transplantation is an option for some patients.

Hepatocellular carcinoma, hepatitis B and C, and some cases of Budd Chiari syndrome and autoimmune liver disease may recur in the transplanted liver. The incidence of recurrence of hepatitis B can be reduced by preoperative and postoperative treatment with lamivudine, adefovir dipivoxil, or entecavir and perioperative administration of HBIG. Immunosuppression is achieved with a combination of cyclosporine or tacrolimus, corticosteroids, azathioprine, and mycophenolate mofetil and may be complicated by infections, renal failure, neurologic disorders, and drug toxicity as well as graft rejection, vascular occlusion, or bile leaks.

Patients are at risk for obesity, diabetes, and hyperlipidemia. Factors determining survival include the patient's ability to stop the intake of alcohol as well as the Child-Turcotte-Pugh class Table The MELD score, which incorporates the serum bilirubin and creatinine levels and the INR, is also a measure of mortality risk in patients with end-stage liver disease and is particularly useful for predicting short- and intermediate-term survival and determining allocation priorities for donor livers.

Hematemesis, jaundice, and ascites are unfavorable signs. The risk of death in this subgroup of patients with advanced cirrhosis is associated with renal insufficiency, cognitive dysfunction, ventilatory insufficiency, P.

Modified Child-Turcotte-Pugh classification for cirrhosis. Albillos A et al: A meta-analysis of transjugular intrahepatic portosystemic shunt versus paracentesis for refractory ascites. Boyer TD et al: The role of transjugular portosystemic shunt in the management of portal hypertension. Cardenas A et al: C rdoba J et al: Treatment of hepatic encephalopathy. D'Amico G et al: Uncovered transjugular intrahepatic portosystemic shunt for refractory ascites: Murray KF et al: Pham PT et al: Aliment Pharmacol Ther ; Sheer TA et al: Swanson KL et al: Natural history of hepatopulmonary syndrome: Elevation of alkaline phosphatase, positive antimitochondrial antibody, elevated IgM, increased cholesterol.

In later stages, can present with fatigue, jaundice, features of cirrhosis, xanthelasma, xanthoma, steatorrhea. Primary biliary cirrhosis is a chronic disease of the liver characterized by autoimmune destruction of intrahepatic bile ducts and cholestasis.

It is insidious in onset, occurs usually in women aged 40 60 years, and is often detected by the chance finding of elevated alkaline phosphatase levels. Estimated incidence and prevalence rates in the United States are 4. The frequency of the disease among first-degree relatives of affected persons is 1.

The disease is progressive and may be complicated by steatorrhea, xanthomas, xanthelasma, osteoporosis, osteomalacia, and portal hypertension.

It may be associated with Sj gren's syndrome, autoimmune thyroid disease, Raynaud's syndrome, scleroderma, hypothyroidism, and celiac disease. Infection with Novosphingobium aromaticivorans or Chlamydia pneumoniae may be triggering or causative in primary P.

Many patients are asymptomatic for years. The onset of clinical illness is insidious and is heralded by fatigue and pruritus. With progression, physical examination reveals hepatosplenomegaly.

Xanthomatous lesions may occur in the skin and tendons and around the eyelids. Jaundice, steatorrhea, and signs of portal hypertension are late findings. The risk of osteopenia and osteoporosis is increased in patients with primary biliary cirrhosis who tend to be older women possibly due in part to polymorphisms of the vitamin D receptor.

Blood counts are normal early in the disease. Liver biochemical tests reflect cholestasis with elevation of alkaline phosphatase, cholesterol especially high-density lipoproteins , and, in later stages, bilirubin. ANAs with distinctive specificities eg, against gp in the nuclear envelope or nucleoporin p62 may be detected in specialized laboratories. The diagnosis of primary biliary cirrhosis is based on the detection of cholestatic liver chemistries often initially an isolated elevation of the alkaline phosphatase and antimitochondrial antibodies in serum.

Liver biopsy is not essential for diagnosis but permits histologic staging: I, portal inflammation with granulomas; II, bile duct proliferation, periportal inflammation; III, interlobular fibrous septa; and IV, cirrhosis.

The disease must be differentiated from chronic biliary tract obstruction stone or stricture , carcinoma of the bile ducts, primary sclerosing cholangitis, sarcoidosis, cholestatic drug toxicity eg, chlorpromazine , and in some cases chronic hepatitis. Patients with a clinical and histologic picture of primary biliary cirrhosis but no antimitochondrial antibodies are said to have autoimmune cholangitis, which has been associated with lower serum IgM levels and a greater frequency of smooth muscle and ANAs.

Many such patients are found to have antimitochondrial antibodies by immunoblot against recombinant proteins rather than standard immunofluorescence. Some patients have overlapping features of primary biliary cirrhosis and autoimmune hepatitis. Treatment is primarily symptomatic. Cholestyramine 4 g or colestipol 5 g in water or juice three times daily may be beneficial for the pruritus. Rifampin, mg orally twice daily, is inconsistently beneficial.

Opioid antagonists eg, naloxone, 0. The 5-hydroxytryptamine 5-HT 3 serotonin receptor antagonist ondansetron may also provide some benefit.

For refractory pruritus, plasmapheresis or extracorporeal albumin dialysis may be needed. Deficiencies of vitamins A, K, and D may occur if steatorrhea is present and is aggravated when cholestyramine or colestipol is administered. See Chapter 26 for discussion on prevention and treatment of osteoporosis.

Ursodeoxycholic acid therapy has also been reported to reduce the risk of recurrent colorectal adenomas in patients with primary biliary cirrhosis. Methotrexate may also improve liver histology in some patients, but overall response rates have been disappointing.

Penicillamine, prednisone, and azathioprine have proved to be of no benefit. Budesonide may improve liver histology but worsens osteopenia. Mycophenolate mofetil is under study. For patients with advanced disease, liver transplantation is the treatment of choice. Without liver transplantation, survival averages 7 10 years once symptoms develop. Progression to liver failure is associated with the presence of anticentromere antibodies.

In advanced disease, adverse prognostic markers are older age, high serum bilirubin, edema, low serum albumin, prolonged prothrombin time, and variceal hemorrhage.

Among asymptomatic patients, at least one-third will become symptomatic within 15 years. The risk of hepatobiliary malignancies appears to P.

Combes B et al: Corpechot C et al: The effect of ursodeoxycholic acid therapy on the natural history of primary biliary cirrhosis. Gershwin ME et al eds: Gershwin ME et al: Risk factors and comorbidities in primary biliary cirrhosis: Kaplan MM et al: Most patients are asymptomatic; the disease is rarely recognized clinically before the fifth decade.

Hemochromatosis is an autosomal recessive disease caused in many cases by a mutation in the HFE gene on chromosome 6.

The alteration leads to substitution of tyrosine for cysteine at position CY in a region of the gene product involved in interaction with 2 -microglobulin. The HFE protein is thought to play an important role in the process by which duodenal crypt cells sense body iron stores. The presence of the mutation apparently reduces surface expression of an HFE 2 -microglobulin complex on duodenal crypt cells, decreasing the affinity of the transferrin receptor for transferrin.

This impairs transferrin-mediated uptake of iron from the circulation into crypt cells and results in up-regulation of duodenal metal-transporter-1 and ferroportin-1 expression on the luminal side of villous cells, leading in turn to increased iron absorption from the intestine. A decrease in the expression of hepcidin, the principal iron regulatory hormone, is also thought to lead to increased ferroportin-1 expression.

By contrast, the gene mutation and hemochromatosis are uncommon in African-American and Asian-American populations. A second genetic mutation leading to substitution of aspartic acid for histidine at position 63 H63D of the same protein may contribute to the development of hemochromatosis in a small percentage 1.

A third HFE mutation, S65C , appears to lead to mild to moderate hepatic iron overload without fibrosis in some cases. Rare instances of hemochromatosis result from mutations in the genes that encode transferrin receptor 2 and ferroprotein. The disorder is characterized by increased accumulation of iron as hemosiderin in the liver, pancreas, heart, adrenals, testes, pituitary, and kidneys. Cirrhosis is more likely to develop in affected persons who drink alcohol excessively or have obesity-related steatosis than in those who do not.

Eventually, hepatic and pancreatic insufficiency, congestive heart failure, and hypogonadism may develop. The disease is rarely recognized clinically before the fifth decade. Heterozygotes do not develop cirrhosis in the absence of associated disorders such as viral hepatitis or NAFLD. A juvenile-onset variant is characterized by severe iron overload, cardiac dysfunction, hypogonadotropic hypogonadism, and a high mortality rate and is infrequently associated with the CY mutation and usually linked to a mutation of a gene on chromosome 1q designated HJV that produces a protein called hemojuvelin or rarely to a mutation in the HAMP gene that encodes hepcidin.

The onset is usually after age 50 years earlier in men than in women; however, because of widespread liver biochemical testing and iron screening, the diagnosis can be made long before symptoms develop. Early symptoms are nonspecific eg, fatigue, arthralgias. Later clinical manifestations include arthropathy, hepatomegaly and evidence of hepatic insufficiency late finding , skin pigmentation combination of slate-gray due to iron and brown due to melanin, sometimes resulting in bronze color , cardiac enlargement with or without heart failure or conduction defects, diabetes mellitus with its complications, and impotence in men.

Interestingly, population studies have shown an increased prevalence of liver disease but not of diabetes, arthritis, or heart disease in CY homozygotes. Affected men are more likely than affected women to have an elevated ferritin level. MRI and CT may show changes consistent with iron overload of the liver, and MRI can quantitate hepatic iron stores; however, these techniques are not sensitive enough for screening. Testing for HFE mutations is indicated in any patient with evidence of iron overload and in siblings of patients with confirmed hemochromatosis.

In patients who are homozygous for CY , liver biopsy is often indicated to determine whether cirrhosis is present. Liver biopsy is also indicated when iron overload is suspected even though the patient is not homozygous for CY.

In patients with hemochromatosis, the liver biopsy characteristically shows extensive iron deposition in hepatocytes and in bile ducts and the hepatic iron index hepatic iron content per gram of liver converted to micromoles and divided by the patient's age is generally greater than 1.

Early diagnosis and treatment in the precirrhotic phase of hemochromatosis are of great importance. Affected patients should avoid foods rich in iron such as red meat , alcohol, vitamin C, raw shellfish, and supplemental iron. This process is monitored by hematocrit and serum iron determinations.

The chelating agent deferoxamine is indicated for patients with hemochromatosis and anemia or in those with secondary iron overload due to thalassemia who cannot tolerate phlebotomies. However, treatment is painful and time-consuming. Complications of hemochromatosis arthropathy, diabetes, heart disease, portal hypertension, and hypopituitarism also require treatment.

The course of the disease is favorably altered by phlebotomy therapy. In precirrhotic patients, cirrhosis may be prevented. Cardiac conduction defects and insulin requirements improve with treatment. In patients with cirrhosis, varices may reverse, and the risk of variceal bleeding declines. However, cirrhotic patients must be monitored for the development of hepatocellular carcinoma. Liver transplantation for advanced cirrhosis associated with severe iron overload, including hemochromatosis, has been reported to lead to survival rates that are lower than those for other types of liver disease because of cardiac complications and an increased risk of infections.

Genetic testing is recommended for all first-degree family members of the proband; children of an affected person CY homozygote need to be screened only if the patient's spouse carries the CY or H63D mutation.

Screening all white men over age 30 years or all adults over age 20 years by measurement of the transferrin saturation or perhaps the unbound iron-binding capacity has been recommended by some, but the value of screening has been questioned on the basis of recent observations that morbidity and mortality from hemochromatosis are lower than expected. Patients with otherwise unexplained chronic liver disease, arthritis, impotence, and late-onset type 1 and possibly type 2 diabetes mellitus should be screened for iron overload.

Adams PC et al: Hemochromatosis and iron-overload screening in a racially diverse population. Bacon BR, guest ed: Iron and the liver. Powell E et al: Steatosis is a cofactor in liver injury in hemochromatosis.

Qaseem A et al: Screening for hereditary hemochromatosis: Schmitt B et al: Screening primary care patients for hereditary hemochromatosis with transferrin saturation and serum ferritin levels: Zoller H et al: Wilson's disease hepatolenticular degeneration is a rare autosomal recessive disorder that usually occurs between the first and third decades. The worldwide prevalence is about 30 per million population. The condition is characterized by excessive deposition of copper in the liver and brain.

The genetic defect, localized to chromosome 13, has been shown to affect a copper-transporting adenosine triphosphatase ATP7B in the liver and leads to copper accumulation in the liver and oxidative damage of hepatic mitochondria. Most patients are compound heterozygotes ie, carry two different mutations. Over different mutations in the Wilson disease gene have been identified, making genetic diagnosis impractical except within families in which the mutation has been identified in the index case.

The major physiologic aberration in Wilson's disease is excessive absorption of copper from the small intestine and decreased excretion of copper by the liver, resulting in increased tissue deposition, especially in the liver, brain, cornea, and kidney.

Serum ceruloplasmin, the plasma copper-carrying protein, is low. Urinary excretion of copper is high. Wilson's disease tends to present as liver disease in adolescents and neuropsychiatric disease in young adults, but there is great variability. The diagnosis should always be considered in any child or young adult with hepatitis, splenomegaly with hypersplenism, Coombs-negative hemolytic anemia, portal hypertension, and neurologic or psychiatric abnormalities.

Wilson's disease should also be considered in persons under 40 years of age with chronic or fulminant hepatitis. Hepatic involvement may range from elevated liver tests although the alkaline phosphatase may be low to cirrhosis and portal hypertension. The neurologic manifestations are related to basal ganglia dysfunction and include a resting, postural, or kinetic tremor and dystonia of the bulbar musculature with resulting dysarthria and dysphagia.

Psychiatric features include behavioral and personality changes and emotional lability. The pathognomonic sign of the condition is the brownish or gray-green Kayser-Fleischer ring, which represents fine pigmented granular deposits in Descemet's membrane in the cornea close to the endothelial surface.

The ring is usually most marked at the superior and inferior poles of the cornea. It can frequently be seen with the naked eye and almost invariably by slit-lamp examination. It may be absent in patients with hepatic manifestations only but is usually present in those with neuropsychiatric disease.

Renal calculi, the Fanconi defect, renal tubular acidosis, hypoparathyroidism, and hemolytic anemia may occur in patients with Wilson's disease. However, increased urinary copper and low serum ceruloplasmin levels are neither completely sensitive nor specific for Wilson's disease. In equivocal cases when the serum ceruloplasmin level is normal , the diagnosis may require demonstration of low radiolabeled copper incorporation into ceruloplasmin or urinary copper determination after a penicillamine challenge.

Liver biopsy may show acute or chronic hepatitis or cirrhosis. MRI of the brain may show increased basal ganglia copper even early in the course of the disease. Early treatment to remove excess copper is essential before it can produce neurologic or hepatic damage.

Early in the treatment phase, restriction of dietary copper shellfish, organ foods, and legumes may be of value. Oral pyridoxine, 50 mg per week, is added, since penicillamine is an antimetabolite of this vitamin.

If penicillamine treatment cannot be tolerated because of gastrointestinal, hypersensitivity, or autoimmune reactions, consider the use of trientine, mg three times a day. Oral zinc acetate, 50 mg three times a day, interferes with intestinal absorption of copper, promotes fecal copper excretion, and may be used as maintenance therapy after decoppering with a chelating agent or as first-line therapy in presymptomatic or pregnant patients.

Ammonium tetrathiomolybdate, which complexes copper in the intestinal tract, has shown promise as initial therapy for neurologic Wilson's disease. Treatment should continue indefinitely. Supplemental vitamin E, an antioxidant, has been recommended P. Ferenci P et al: Diagnostic value of quantitative hepatic copper determination in patients with Wilson's disease.

Medici V et al: Liver transplantation for Wilson's disease: Occlusion of the hepatic veins may occur from a variety of causes. Many cases are associated with polycythemia vera or other myeloproliferative diseases, which may be subclinical. In some cases, an underlying predisposition to thrombosis eg, hyperprothrombinemia [factor II GA mutation], activated protein C resistance [factor V Leiden mutation], protein C or S or antithrombin deficiency, the methylenetetrahydrofolate reductase mutation, antiphospholipid antibodies can be identified.

Hepatovenous obstruction may be associated with caval webs, right-sided heart failure or constrictive pericarditis, neoplasms that cause hepatic vein occlusion, paroxysmal nocturnal hemoglobinuria, Beh et's syndrome, blunt abdominal trauma, use of oral contraceptives, and pregnancy.

Some cytotoxic agents and pyrrolizidine alkaloids bush teas may cause sinusoidal obstruction syndrome previously known as veno-occlusive disease because the terminal venules are occluded , which mimics Budd Chiari syndrome clinically.

Sinusoidal obstruction syndrome is common in patients who have undergone bone marrow transplantation, particularly those with pretransplant aminotransferase elevations or fever during cytoreductive therapy with cyclophosphamide, azathioprine, carmustine, busulfan, or etoposide or those receiving high-dose cytoreductive therapy or high-dose total body irradiation. In India, China, and South Africa, Budd Chiari syndrome is often the result of occlusion of the hepatic portion of the inferior vena cava, presumably due to prior thrombosis, and the clinical presentation is mild but the course is frequently complicated by hepatocellular carcinoma.

The presentation may be fulminant, acute, subacute, or chronic. An insidious subacute onset is most common. Clinical manifestations generally include tender, painful hepatic enlargement, jaundice, splenomegaly, and ascites. With chronic disease, bleeding varices and hepatic coma may be evident; hepatopulmonary syndrome may occur.

Hepatic imaging studies may show a prominent caudate lobe, since its venous drainage may not be occluded. MRI with spin-echo and gradient-echo sequences and intravenous gadolinium injection allows visualization of the obstructed veins and collateral vessels.

Direct venography can delineate caval webs and occluded hepatic veins spider-web pattern most precisely. Percutaneous or transjugular liver biopsy frequently shows a characteristic centrilobular congestion and fibrosis and often multiple large regenerating nodules. Liver biopsy is often contraindicated in sinusoidal obstruction syndrome because of thrombocytopenia, and the diagnosis is based on clinical findings.

Ascites should be treated with fluid and salt restriction and diuretics. Treatable causes of Budd Chiari syndrome should be sought. Prompt recognition and treatment of an underlying hematologic disorder may P.

Bogin V et al: Eur J Gastroenterol Hepatol ; Molmenti EP et al: Murad SD et al: Pathogenesis and treatment of Budd-Chiari syndrome combined with portal vein thrombosis. Ruh J et al: Management of Budd-Chiari syndrome. Senzolo M et al: Update on the classification, assessment of prognosis and therapy of Budd-Chiari syndrome.

Nat Clin Pract Gastroenterol Hepatol ;2: Shock liver, or ischemic hepatopathy, results from an acute fall in cardiac output due, for example, to acute myocardial infarction or arrhythmia, usually in a patient with passive congestion of the liver. Clinical hypotension may be absent or unwitnessed.

In some cases, the precipitating event is arterial hypoxemia due to respiratory failure. The prothrombin time may be prolonged, and encephalopathy may develop. The mortality rate due to the underlying disease is high, but in patients who recover, the aminotransferase levels return to normal quickly, usually within 1 week in contrast to viral hepatitis.

Serum alkaline phosphatase levels are normal or slightly elevated.

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