Is Ther Cell Service On Lake Powell
J Hepatol. Author manuscript; bachelor in PMC 2012 Sep 1.
Published in concluding edited form as:
PMCID: PMC3139780
NIHMSID: NIHMS272827
Presence and Significance of Microvesicular Steatosis in Nonalcoholic Fatty Liver Disease
Sweta Tandra
iIndiana University School of Medicine, Indianapolis, IN
Matthew 1000. Yeh
2University of Washington Schoolhouse of Medicine, Department of Pathology, Seattle, WA
Elizabeth G. Brunt
threeWashington University Schoolhouse of Medicine, Section of Pathology and Immunology, St. Louis, MO
Raj Vuppalanchi
1Indiana University School of Medicine, Indianapolis, IN
Oscar W. Cummings
1Indiana Academy Schoolhouse of Medicine, Indianapolis, IN
Aynur Ünalp-Arida
4Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
Laura A. Wilson
4Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
Naga Chalasani
1Indiana University School of Medicine, Indianapolis, IN
Abstruse
Background/Aims
Liver biopsies from patients with nonalcoholic fatty liver affliction (NAFLD) sometimes exhibit non-zonal aggregates of hepatocytes with microvesicular steatosis, but its prevalence and significance are unclear. In this study, we have evaluated the frequency of microvesicular steatosis and assessed its clan with histological markers of illness severity in a large sample of NAFLD liver biopsies.
Methods
Liver biopsies from a large accomplice of adults who participated in two studies conducted by the NASH Clinical Inquiry Network (NASH CRN) were included in this cross-sectional report. Liver histology was assessed centrally and various histological features scored in a systematic fashion. The relationship betwixt microvesicular steatosis and various histological features that characterize NAFLD was tested by multiple logistic regression, afterward decision-making for historic period, gender, race, trunk mass index, and diabetes.
Results
Among 1022 liver biopsies included, 102 (10%) had microvesicular steatosis. No demographic differences were noted between patients with or without microvesicular steatosis. The presence of microvesicular steatosis was associated with higher grades of steatosis (p<0.001), ballooning prison cell injury (p<0.001), presence of Mallory-Denk bodies (p<0.007), presence of megamitochondria (p<0.0001), higher NAS scores (p<0.0001), more than advanced fibrosis (p<0.0001) and diagnosis of borderline or definite NASH (p<0.0001).
Determination
Microvesicular steatosis correlates with more advanced histology of NAFLD. Longitudinal studies are needed to address the function of microvesicular steatosis in mediating cellular injury and disease progression in NAFLD.
Keywords: Microvesicular steatosis, fatty liver, NASH, lipid droplets
INTRODUCTION
Nonalcoholic fatty liver disease (NAFLD) is a well-defined clinico-pathological entity which encompasses a histologic spectrum ranging from a relatively benign steatosis or nonalcoholic fat liver (NAFL) to a potentially progressive and aggressive form termed nonalcoholic steatohepatitis (NASH) [19, 21, 22]. NAFLD is oft associated with characteristics of the metabolic syndrome and is considered to be the hepatic manifestation of the metabolic syndrome. Amidst obese patients, approximately 60% have steatosis, 20%–25% have NASH, and cirrhosis may be present in 2%–iii% [2, iii, xi, 14]. Nonalcoholic steatohepatitis is characterized by the presence of inflammation and cell injury, i.e., hepatocyte ballooning, chronic inflammatory cell infiltrates and Mallory-Denk bodies, with or without fibrosis. Accumulating evidence from several cross-sectional studies suggests that oxidative stress plays a key role in the pathogenesis of NASH but it is not clear if this is the cause or consequence of liver injury. Information technology was shown that there is stiff correlation between the markers of oxidative stress, lipid peroxidation products and severity of NASH [1, fourteen, 25]. Although, there are several studies that identified various histological and non-histological variables to predict the presence of advanced histology in cantankerous-sectional studies. To our cognition, in that location are very few prospective studies that examined the significance of diverse histological features in the disease progression longitudinally.
Steatosis in NAFLD is commonly seen as macrovesicular steatosis (big droplet steatosis) in which a unmarried, big vacuole of fatty fills up the hepatocyte and displaces the nucleus to the periphery. Often macrovesicular steatosis can exist present with both large and small droplets that may be seen to coalesce. Macrovesicular steatosis alone is considered to accept a skilful long-term prognosis with rare progression to fibrosis or cirrhosis. On the other hand, diffuse microvesicular steatosis denotes a separate clinical entity commonly characterized past encephalopathy and liver failure; the diseases share severe mitochondrial β-oxidation defects from genetic or caused causes. Examples include acute fat liver of pregnancy, Reyes syndrome, drugs or toxins [12, 13]. These diseases either resolve, or end in death if not managed with liver transplant; unlike NAFLD, these processes do not pb to chronic liver illness and cirrhosis. Histologically, microvesicular steatosis is characterized by distended hepatocytes with foamy appearing cytoplasm; small lipid vesicles (less than 1µm in diameter) may or may not exist discernible. The nucleus is typically centrally located unlike in macrovesicular steatosis where the nucleus is displaced peripherally. Because of the lengthened cytoplasmic alteration, special staining such as oil red O may be required for its diagnosis. Microvesicular steatosis is also unremarkably present in the same hepatocytes that harbor visualizable mitochondria, known as "megamitochondria".
Some liver biopsies from patients with NAFLD exhibit not-zonal aggregates of microvesicular steatosis. The significance of this finding, however, is not articulate. Therefore, we conducted a study to examine the (a) prevalence of microvesicular steatosis in a large collection of well-characterized NAFLD liver biopsies and (b) relationship betwixt microvesicular steatosis and various histological features that characterize NAFLD.
METHODS
This written report was conducted on available liver biopsies from adult patients (historic period ≥ 18 years at time of biopsy) who were enrolled in the Nonalcoholic Fatty Liver Disease (NAFLD) Database study or the Pioglitazone vs. Vitamin E vs. Placebo for the Treatment of Non-diabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial conducted by the NASH Clinical Research Network (NASH CRN). The NAFLD Database is a prospective, observational written report of patients with definite NAFLD, suspected NAFLD, definite cryptogenic cirrhosis, and suspected (clinical) cryptogenic cirrhosis. Patients with steatosis involving ≥ 5% hepatic parenchyma on liver biopsy with no significant alcohol consumption or other coexisting etiologies (e.thou., autoimmune liver disease, hemochromatosis, primary biliary cirrhosis, etc.) were defined every bit having NAFLD. Significant booze consumption was defined as > 14 drinks/week in men or >vii drinks/week in women on average within the preceding 2 years. The details of booze consumption were obtained by physician interviews and by administration of the Alcohol Use Disorders Identification Exam (Inspect) and the Skinner Lifetime Drinking History questionnaires. PIVENS is a multi-center, randomized, placebo-controlled, double-masked clinical trial of treatment with pioglitazone, vitamin Due east, or placebo for not-diabetic patients with histologically-confirmed NASH. Merely the liver biopsies taken prior to randomization and treatment were included in this written report.
The Institutional Review Boards at each Clinical Center, including Indiana University School of Medicine, and the Data Coordinating Center reviewed and approved the protocols and each patient has signed an informed consent.
Clinical data
The demographic and clinical data were nerveless within 6 months of liver biopsy, including age at enrollment, gender, race, height, weight, history of diabetes, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Torso mass index (BMI) was calculated as weight (Kg)/acme (m2) and HOMA IR (Homeostasis Model Assessment for Insulin Resistance) was calculated in not-diabetic patients using simultaneously obtained fasting serum glucose and insulin using the formula: HOMA = (glucose [mmol/L]* insulin[µU/mL])/22.v).
Histopathological data
All liver biopsies were reviewed and centrally scored by the Pathology Committee co-ordinate to the NASH CRN scoring organization [16]. Hematoxylin and Eosin (H&E) staining (for all features except fibrosis) and Masson's trichrome staining (fibrosis but) were used to perform the evaluations. The post-obit histological features were considered for our study:
Steatosis
Macrovesicular steatosis
Graded from 0–iii based on the percentage of hepatocytes involved (0 = <5%; ane = v%–33%; 2 = 33%–66%; three = >66%). The cess of macrovesicular steatosis was commonly done at 4× magnification (at most 10× magnification was used).
Microvesicular steatosis
Reported as beingness either present or absent. Initial assessment was done under lower magnification (4× to 10×) and confirmed under higher magnification, if necessary. Microvesicular steatosis was divers as the presence of non-zonal, face-to-face patches of "foamy hepatocytes with centrally placed nuclei" on an H&E stained slide under light microscopy (Figures 1 and 2).
H and Due east stained sections shows microvesicular steatosis and scattered mixed small and big droplet macrovesicular along the right; note the compatible involvement of hepatocytes. The hepatocytes take an almost "foamy" appearance
Trichrome stained slide showing a patch of microvesicular steatosis in zone three. Megamitochondria tin be observed (arrows).
Lobular inflammation
Lobular inflammation was graded from 0–3 based on inflammatory foci per twenty× magnification (0 = none; 1 = ane–2/20×; ii = up to 4/20×; 3 = >4/20×).
Ballooning
Hepatocyte ballooning was express to three categories (0 = none, 1 = few or 2 = many) based on the reproducible cutting-off points as described previously [sixteen].
NAFLD action score (NAS score)
NAS score was calculated from the sum of scores for steatosis (0–3), lobular inflammation (0–3) and hepatocyte ballooning (0–2).
Fibrosis
was graded based on the modified Brunt classification; 0 = no fibrosis, i = perisinusoidal or periportal fibrosis, ii = both perisinusoidal and periportal fibrosis, 3 = bridging fibrosis, iv = cirrhosis [5].
Boosted Features
Other histological features such as megamitochondria and presence of Mallory-Denk bodies were graded on a ii-point scale equally either 0 (none/rare) or 1 (many).
Diagnosis of NASH
Diagnosis of steatohepatitis was based on pattern recognition and was categorized into three groups: not NASH, borderline NASH or definite NASH.
Statistical methods
Baseline patient characteristics were compared across the two groups (presence and absence of microvesicular steatosis) using chi-foursquare tests for chiselled variables (Fisher's Verbal Test was used for race, due to small expected numbers), and the Wilcoxon rank-sum test for continuous measures. Nominal, two-sided P-values were used and were considered to exist statistically meaning if P<0.05. The human relationship between the presence of microvesicular steatosis and dissimilar histological features including grades of macrovesicular steatosis, lobular inflammation, hepatocyte ballooning, fibrosis, Mallory bodies, megamitochondria, NAS score, steatohepatitis diagnosis, and selected biochemical values such as AST and ALT was explored using multiple logistic regression analyses. Using the presence vs. absence of microvesicular steatosis as the event mensurate, split logistic regression models were fit for each of the histological features listed above, decision-making for historic period at enrollment (years), gender, race (Caucasian vs. other), BMI (kg/yard2), and presence of diabetes. All analyses were performed using SAS statistical software (version 9.i, SAS Institute, Cary, NC) and Stata (Release 10.0, Stata Corporation, Higher Station, Texas).
RESULTS
Demographic and clinical information
Microvesicular steatosis was present by light microscopy in 102 of 1022 liver biopsies (x%) reviewed. When groups with and without microvesicular steatosis were compared, there were no meaning differences in demographic and clinical features, including historic period, sex, race/ethnicity, presence of diabetes, BMI, or serum aminotransferase levels (Table 1). In that location was statistically significantly relationship between the length of liver biopsy and the presence of microvesicular steatosis. The median (25th, 75th percentile) length of liver biopsies with microvesicular steatosis was significantly higher than length of biopsies without microvesicular steatosis (20 (16–25) mm vs, 16 (xi–24) mm, p<0.0001).
Table 1
Baseline patient characteristics and selected clinical data of patients (due north=1022)
| Microvesicular Steatosis | |||
|---|---|---|---|
| Present (northward=102) | Absent-minded (n=920) | p-value® | |
| Historic period at enrollment (yrs) | 50.ii ±12.five | 49.5 ± 11.9 | 0.4 |
| Females (%) | 66 | 63 | 0.six |
| Caucasians (%) | 88 | 84 | 0.v |
| BMI (kg/chiliad2)€ | 36.1 ± seven.vi | 34.4 ±6.4 | 0.ane |
| Diabetes (%) | 24.5 | 29.5 | 0.iii |
| HOMA–IR† | 4.4 (3.iv–5.9) | 4.0 (ii.6–half-dozen.three) | 0.3 |
| AST (U/L)* | fifty (36–71) | 45 (32–65) | 0.07 |
| ALT (U/L)* | 63 (46–102) | 65 (43–97) | 0.vi |
Microvesicular steatosis and histological features of NASH
a. Macrovesicular steatosis, lobular inflammation, hepatocyte ballooning and fibrosis
Microvesicular steatosis was present across all grades of macrovesicular steatosis, just was clearly associated with more than severe macrovesicular steatosis (Table 2). In contrast, there was no pregnant association betwixt microvesicular steatosis and presence or degree of lobular inflammation. However, there was an association between the presence of microvesicular steatosis and hepatocyte ballooning, as microvesicular steatosis was seen at a significantly higher frequency in liver biopsies with few ballooned hepatocytes (OR: 3.0, 95% CI-one.5–5.viii), and with even greater frequency in liver biopsies with many ballooned hepatocytes (OR: three.6, 95% CI ii.0–six.eight). Finally, the presence of microvesicular steatosis was significantly associated with more advanced fibrosis (Grade 3 and four combined) (OR: 2.3, 95%, CI: 1.4–three.6).
Table 2
Relationship between microvesicular steatosis and histological features of NASH from multiple logistic regression analysis
| Total N | % with Microvesicular Steatosis | Odds Ratio (95% CI) | p-value | |
|---|---|---|---|---|
| Steatosis | ||||
| <5% (reference) | 65 | iii.ane% | ||
| 5–33% | 401 | 7.0% | 2.2 (0.5–nine.5) | |
| 34–66% | 318 | 10.4% | 3.6 (0.8–xv.iv) | <0.001 |
| >66% | 238 | sixteen.four% | vi.four (i.5–27.4) | |
| | ||||
| Lobular inflammation | ||||
| <2 under 20X magazine (reference)¶ | 538 | ix.1% | ||
| 2–four nether 20Xmag | 372 | xi.3% | 1.ii (0.8–1.9) | 0.68 |
| >4 under 20Xmag | 112 | 9.8% | 1.two (0.6–2.5) | |
| | ||||
| Ballooning | ||||
| None (reference) | 340 | 4.4% | ||
| Few | 260 | 11.9% | 3.0 (one.5–5.eight) | <0.001 |
| Many | 422 | 13.3% | 3.vi (2.0–6.8) | |
| | ||||
| Fibrosis stage | ||||
| 0: None (reference) | 249 | iv.0% | ||
| ane: Zone three or portal/periportal | 274 | seven.3% | 1.6 (0.7–iii.6) | |
| 2: Zone iii and periportal | 180 | 14.iv% | 4.iii (two.0–9.3) | <0.0001 |
| 3: Bridging | 204 | 13.7% | 4.4 (2.0–9.six) | |
| four: Cirrhosis | 107 | 15.ix% | 5.vii (ii.iv–13.6) | |
| | ||||
| Megamitochondria | ||||
| Rare/Absent (reference) | 860 | 6.7% | five.0 (three.1–7.nine) | <0.0001 |
| Many | 162 | 27.2% | ||
| | ||||
| Mallory-Denk bodies | ||||
| Rare/absent (reference) | 723 | 8.6% | ||
| Present | 299 | 13.4% | 1.9 (one.ii–2.nine) | <0.007 |
| | ||||
| NAFLD Action Score (NAS, range 0–eight) | 4.iv±1.7 | ane.iv(1.2–1.vi) | <0.0001 | |
| | ||||
| Presence of NASH | ||||
| No (reference) | 230 | 1.7% | ||
| Borderline/Suspicious | 206 | 8.7% | 6.9 (2.0–23.9) | <0.0001 |
| Definite | 585 | 13.7% | 12.0 (3.7–38.viii) | |
b. Megamitochondria and Mallory-Denk bodies
The odds of finding microvesicular steatosis were i.nine times greater in liver biopsies with Mallory-Denk bodies (95% CI: 1.2–2.9) compared with biopsy samples without. Similarly, there was a strong relationship between microvesicular steatosis and the presence of megamitochondria (OR: 5.0, 95% CI: three.1–7.nine) (Table 2).
c. NAS and diagnosis of NASH
At that place was a articulate association of the presence of microvesicular steatosis and increasing NAS scores. For every 1-point increase in NAS score, there was a 1.four-fold increase in the likelihood of observing microvesicular steatosis (95% CI: one.2–one.half-dozen, p<0.0001). There was as well a strong relationship between microvesicular steatosis and a diagnosis of NASH. Thus, in comparing to "not NASH", the odds ratio for borderline NASH was six.7(95% CI: 2.0–three.vii, p<0.0001) and 12.0 for definite NASH (95% CI: 3.seven – 38.8, p<0.0001) (Table 2).
Give-and-take
To our noesis, this is outset study to evaluate the presence and significance of microvesicular steatosis in relation to common and well-established histological features of NASH. It describes the findings of a large, multicenter report of liver biopsies from patients with well-characterized NAFLD. Our report makes several of import observations that add incremental knowledge to our understanding of NAFLD and NASH.
The Pathology Committee of the NASH CRN has taken significant caution in defining different types of steatosis; microvesicular steatosis, in particular, is a finding that describes clusters of foamy hepatocytes distributed in an azonal blueprint. These foamy actualization "microvesicular patches" are different from the pocket-sized and/or the medium sized droplets that are seen with macrovesicular steatosis of NAFLD.
It has been hypothesized that large fatty aerosol are formed past the fusion of small aerosol initially plant on the surface of endoplasmic reticulum [four, xx]. The strong relationship we noted betwixt micro-and macrovesicular steatosis is indirectly supportive of this hypothesis, but due to its cantankerous-sectional study design, our study is non able to discern the longitudinal relationship between micro-and macrovesicular steatosis.
There appears to exist contrasting association between micro- and macrovesicular steatosis and histological markers of NASH such every bit hepatocyte ballooning, Mallory bodies and fibrosis. In this study, the presence of microvesicular steatosis was significantly associated with histological hallmarks of cellular injury and cytoskeletal harm such every bit hepatocyte ballooning and Mallory-Denk bodies. This is in contrast to macrovesicular steatosis which does not consistently correlate with features of cell injury and steatohepatitis. For example, in an earlier study from our group, we failed to detect significant relationship between higher grades of macrovesicular steatosis and prominent degrees of ballooning or Mallory-Denk bodies [10]. Interestingly, we constitute a meaning association betwixt the presence of microvesicular steatosis and advanced fibrosis. This finding also differs with the widely recognized finding that macrovesicular steatosis may disappear as the illness progresses into advanced fibrosis and cirrhosis [21, 24]. It is unclear if this finding suggests different etiology for the small-scale droplets or regression in the size of lipid droplets with increasing fibrosis or implies that microvesicular steatosis, rather than macrovesicular steatosis, is an independent predictor of advanced forms of NASH.
Hepatocellular ballooning is an important histological parameter in the diagnosis of NASH and a few longitudinal studies have confirmed information technology to be a major distinguishing feature indicating a greater risk of disease progression [6, 21, 26]. In a recent study published past Caldwell et al, the ballooned hepatocytes were examined by H & E stain, fat-specific oil red stain, anti-keratin-18 immunohistochemistry stained sections and they are establish to have multiple small lipid aerosol, megamitochondria, dilated endoplasmic reticulum, mallory-denk bodies and cytoskeletal damage suggested by keratin-xviii deficiency [7]. These pocket-sized intrahepatocelluar lipid aerosol have limiting phospholipid membranes that are shown to exist the site of initiation of oxidative stress, a process implicated in the pathogenesis of NASH. In a study, Ikura et al demonstrated that oxidized phosphotidylcholine (oxidatively damaged phospholipid) was seen at the surface of the pocket-size lipid droplet within the ballooned hepatocytes suggesting that the source of oxidative injury is the small lipid droplet [15]. This unifies the concept of oxidative stress mediated injury to hepatocyte and the pathogenic role of small-scale lipid droplet. The strong association seen betwixt microvesicular steatosis, hepatocellular ballooning and mallory denk bodies in our study leads to a plausible explanation that the presence of microvesicular steatosis on a H & Eastward stain may represent a severe form of NASH. Information technology is as well possible that oxidative injury may be the deviation betwixt microvesicular steatosis and ballooning degeneration.
Diffuse microvesicular steatosis denotes a divide clinical entity with a grave prognosis and is more often than not attributed to severe genetic or acquired defects in mitochondrial β-oxidation [12, thirteen]. Megamitochondria are regarded equally the most hitting modify in the mitochondrial morphology observed in at to the lowest degree 5–15% of hepatocytes distributed in azonal fashion in NASH patients [8, 9, 18]. Commonage data from previous studies indicate that mitochondrial morphological features reverberate a true functional impairment in the mitochondria [17, 23] while a few studies advise that their presence only represent an adaptive process to oxidative stress. As we observed pregnant clan between megamitochondria and microvesicular steatosis, it is tempting to speculate that presence of both these histological features may betoken significant mitochondrial dysfunction.
There are some limitations to our study. Given that this is a cross-sectional study, it is not possible to assess the impact of microvesicular steatosis on disease progression and outcomes. This possibility is all-time answered with longitudinal study of NAFLD patients with well characterized hepatic histology. The other limitation is that our histological evaluation was washed by H&E stain nether low-cal microscopy at lower magnifications and thus the true prevalence of microvesicular steatosis may exist underreported in this study. Fatty specific oil carmine O stains are better predictors of the prevalence of lipid droplets. Drugs and toxins such as alcohol have been oftentimes implicated in microvesicular steatosis. Although significant alcohol consumption has been systematically excluded in all the patients, a detailed medication history is not obtained. However, drug induced microvesicular steatosis may be less likely a confounder in 10% of microvesicular steatosis group as it tends to be clinically astute and histologically diffuse oftentimes leading to death.
The strengths of our study are the fundamental review process which involves at least 5 liver pathologists and the fact that the foci of microvesicular steatosis were carefully discerned on routine histochemical staining, as is done by all histology laboratories. Another strength is that this is a large series of very carefully characterized patients from multiple centers.
In summary, microvesicular steatosis is seen upwards to 10% of liver biopsies in patients with NAFLD and its presence signifies avant-garde histological features such as ballooning, inflammation, steatohepatitis, and fibrosis. Longitudinal studies are needed to further characterize the role of microvesicular steatosis in the progression of liver disease in patients with NAFLD. If other groups can reproduce our findings, then microvesicular steatosis should be systemically looked for and reported by pathologists when they are examining the liver biopsies from patients with NAFLD.
ACKNOWLEDGEMENTS
The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) is supported by the National Constitute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grants U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, U01DK061713), and the National Institute of Child Wellness and Homo Development (NICHD). Several clinical centers use support from General Clinical Enquiry Centers or Clinical and Translational Scientific discipline Awards in conduct of NASH CRN Studies (grants UL1RR024989, M01RR000750, M01RR00188, UL1RR02413101, M01RR000827, UL1RR02501401, M01RR000065, M01RR020359). Following are the all the members of the NASH CRN who were instrumental in conducting the study at each of the participating institutions: Clinical Centers: Baylor College of Medicine, Houston, TX: Stephanie Abrams, MD; Diana Arceo, MD, MS; Denise Espinosa; Leanel Angeli Fairly, RN; Case Western Reserve University Clinical Centers: MetroHealth Medical Center, Cleveland, OH: Arthur J. McCullough, MD; Patricia Brandt; Diane Bringman, RN (2004–2008); Srinivasan Dasarathy, MD; Jaividhya Dasarathy, MD; Ballad Hawkins, RN; Yao-Chang Liu, MD (2004–2009); Nicholette Rogers, PhD, PA-C (2004–2008); Margaret Stager, Doc (2004–2009); Cleveland Clinic Foundation, Cleveland, OH: Arthur J. McCullough, Doc; Srinivasan Dasarathy, MD; Mangesh Pagadala, Doc; Ruth Sargent, LPN; Lisa Yerian, Physician; Claudia Zein, MD; California Pacific Medical Center: Raphael Merriman, MD; Anthony Nguyen; Children'south National Medical Center, Washington DC: Parvathi Mohan, MD; Kavita Nair; Cincinnati Children's Hospital Medical Centre, Cincinnati, OH: Stephanie DeVore; Rohit Kohli, Doc; Kathleen Lake; Stavra Xanthakos, Md; Knuckles University Medical Center, Durham, NC: Manal F. Abdelmalek, Doctor; Stephanie Buie; Anna Mae Diehl, Physician; Marcia Gottfried, Doc (2004–2008); Cynthia Guy, Dr.; Meryt Hanna; Paul Killenberg, MD (2004–2008); Samantha Kwan, MS (2006–2009); Yi-Ping Pan; Dawn Piercy, FNP; Melissa Smith; Indiana University School of Medicine, Indianapolis, IN: Elizabeth Byam, RN; Naga Chalasani, MD; Oscar W. Cummings, Medico; Ann Klipsch, RN; Jean P. Molleston, MD; Linda Ragozzino, RN; Girish Subbarao, Medico; Raj Vuppalanchi, MD; Johns Hopkins Hospital, Baltimore, Dr.: Kimberly Pfeifer, RN; Ann Scheimann, MD; Michael Torbenson, MD; Mount Sinai Kravis Children's Hospital: Nanda Kerkar, MD; Sreevidya Narayanappa; Frederick Suchy, MD; Northwestern Academy Feinberg School of Medicine/Children's Memorial Hospital: Mark H. Fishbein, MD; Katie Jacques; Ann Quinn, RD; Cindy Riazi, RN; Peter F. Whitington, Physician; Seattle Children's Infirmary & Research Institute, WA: Melissa Coffey; Sarah Galdzicka, Karen Murray, MD; Melissa Young; Saint Louis University, St Louis, MO: Sarah Barlow, MD (2002–2007); Jose Derdoy, MD; Joyce Hoffmann; Debra Male monarch, RN; Andrea Morris; Joan Siegner, RN; Susan Stewart, RN; Brent A. Neuschwander-Tetri, Dr.; Judy Thompson, RN; University of California San Diego, San Diego, CA: Cynthia Behling, Doc, PhD; Janis Durelle; Tarek Hassanein, Dr. (2004–2009); Joel East. Lavine, MD, PhD; Rohit Loomba, MD; Anya Morgan; Steven Rose, MD (2007–2009); Heather Patton, Dr.; Jeffrey B. Schwimmer, Doctor; Claude Sirlin, MD; Tanya Stein, Doc (2005–2009); Academy of California San Francisco, San Francisco, CA: Bradley Aouizerat, PhD; Kiran Bambha, MD (2006–2010); Nathan Yard. Bass, Physician, PhD; Linda D. Ferrell, MD; Danuta Filipowski, Doctor; Bo Gu (2009–2010); Raphael Merriman, Medico (2002–2007); Mark Pabst; Monique Rosenthal (2005–2010); Philip Rosenthal, Doc; Tessa Steel (2006–2008); University of Washington Medical Middle, Seattle, WA: Matthew Yeh, Md, PhD; Virginia Commonwealth Academy, Richmond, VA: Sherry Boyett, RN, BSN; Melissa J. Contos, MD; Michael Fuchs, Doc; Amy Jones; Velimir AC Luketic, MD; Puneet Puri, Doctor; Bimalijit Sandhu, MD (2007–2009); Arun J. Sanyal, Doctor; Carol Sargeant, RN, BSN, MPH; Kimberly Noble; Melanie White, RN, BSN (2006–2009);Virginia Mason Medical Center, Seattle, WA: Kris V. Kowdley, MD; Jody Mooney, MS; James Nelson, PhD; Sarah Ackermann; Cheryl Saunders, MPH; Vy Trinh; Chia Wang, Doc; Washington University, St. Louis, MO: Elizabeth Yard. Burden, Md; Resources Centers: National Cancer Institute, Bethesda, Md: David E. Kleiner, MD, PhD; National Institute of Child Wellness and Man Development, Bethesda, Doctor: Gilman D. Grave, Doc; National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md: Edward C. Doo, MD; Jay H. Hoofnagle, Doctor; Patricia R. Robuck, PhD, MPH (Project Scientist); Johns Hopkins University, Bloomberg School of Public Health (Information Coordinating Center), Baltimore, Physician: Patricia Belt, BS; Frederick L. Brancati, Medico, MHS (2003–2009); Jeanne 1000. Clark, Dr., MPH; Ryan Colvin, MPH; Michele Donithan, MHS; Mika Light-green, MA; Rosemary Hollick (2003–2005); Milana Isaacson, BS; Wana Kim, BS; Alison Lydecker, MPH (2006–2008), Pamela Mann, MPH (2008–2009); Laura Miriel; Alice Sternberg, ScM; James Tonascia, PhD; Aynur Ünalp-Arida, Medico, PhD; Mark Van Natta, MHS; Ivana Vaughn, MPH; Laura Wilson, ScM; Katherine Yates, ScM
Abbreviations
| NAFLD | Nonalcoholic fatty liver disease |
| NASH | Nonalcoholic steatohepatitis |
| PIVENS | Pioglitazone vs. Vitamin East vs. Placebo for the handling of Non-diabetic patients with NASH |
| NASH CRN | Nonalcoholic Steatohepatitis Clinical Research Network |
Footnotes
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CONFLICTS OF INTEREST:
Guarantor of the article: Naga Chalasani, Doctor.
Specific writer contributions: All the members of the NASH CRN were involved in the study design and data acquisition; Data analysis and statistical support were provided by Laura A Wilson; Drs Tandra, Chalasani and Vuppalanchi were involved in the data collection, data assay, data estimation and manuscript grooming. Drs Yeh, Cummings, Unalp-Arida were involved in the grooming of the manuscript. Dr. Elizabeth Brunt participated in the manuscript preparation and critical revision of the article; All of the authors drafted, edited and canonical the final manuscript typhoon.
Potential competing interests: The authors declare that they do not have anything to disembalm regarding funding from industries or conflicts of involvement with respect to this manuscript.
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Is Ther Cell Service On Lake Powell,
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139780/
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