liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Non-Alcoholic Fatty Liver Disease: A clinical and histopathological study
Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Fatty liver has previously often been associated with excessive alcohol consumption. During the last two decades, the interest in fatty liver occurring in non-drinkers i.e. non-alcoholic fatty liver disease (NAFLD) has increased dramatically. Today, NAFLD is considered as the most common liver disease in the developed world. It is strongly associated with obesity, insulin resistance, and hypertension. Thus, NAFLD is considered as the hepatic manifestation of the metabolic syndrome.

The spectrum of NAFLD includes: simple fatty liver without necroinflammatory activity; non-alcoholic steatohepatitis (NASH), a condition characterised by hepatocellular injury, inflammation, and fibrosis; cirrhosis; and in some individuals hepatocellular carcinoma.

The degree of steatosis in liver biopsies is usually assessed by a morphological semiquantitative approach in which the pathologist uses a four-graded scale: 0–3 or none, slight, moderate and severe. In this thesis we show that there is a considerable inter- and intraindividual variation in such scoring methods and that a more standardised and quantitative approach is preferable. The area/volume of fat in liver biopsies is greatly overestimated when assessed semiquantitatively. Moreover, the point counting technique has a better reproducibility than visual evaluation and should be preferred in estimates of liver steatosis.

The long-term clinical and histopathological course of 129 consecutively enrolled NAFLD patients was studied. Mean follow-up (SD) was 13.7 (1.3) years. Survival of NASH patients was reduced compared with a matched reference population. These subjects more often died from cardiovascular and liver-related causes. Seven patients (5.4%) developed end-stage liver disease, including 3 patients with hepatocellular carcinoma. Most NAFLD patients will develop diabetes or impaired glucose tolerance in the long term. Progression of liver fibrosis is associated with more pronounced insulin resistance and significant weight gain.

During follow-up, 17 patients had been prescribed a statin. At follow-up, patients on medication with statins had significantly higher BMI. Diabetes was significantly more common among patients on medication with statins and they had significantly more pronounced insulin resistance. However, they exhibited a significant reduction of liver steatosis at follow-up as opposed to patients not taking statins. Although patients under statin treatment exhibited a high risk profile for progression of liver fibrosis, only four patients on statin treatment progressed in fibrosis stage. It is concluded that statins can be prescribed safely in patients with elevated liver enzymes because of NAFLD.

Alcohol consumption was evaluated with a validated questionnaire combined with an oral interview. In a multivariate analysis moderate alcohol consumption, particularly when frequency of heavy episodic drinking was analysed, consistent with the diagnosis of NAFLD to be set, was independently associated with fibrosis progression in NAFLD.

The NAFLD activity score (NAS) is a newly proposed system to grade the necroinflammatory activity in liver biopsies of NAFLD patients. We evaluated the usefulness of the NAS in predicting clinical deterioration and fibrosis progression in our cohort of NAFLD patients. Although the NAS was independently associated with future risk of progressive fibrosis in NAFLD, the clinical usefulness of the score was limited due to significant overlap in clinical development between NAS-score groups.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2008. , 87 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1081
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:liu:diva-17220ISBN: 978-91-7393-787-0 (print)OAI: oai:DiVA.org:liu-17220DiVA: diva2:207506
Public defence
2008-10-17, Berzeliussalen, CampUS, Hälsouniversitetet, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2009-03-18 Created: 2009-03-11 Last updated: 2012-03-22Bibliographically approved
List of papers
1. Semiquantitative evaluation overestimates the degree of steatosis in liver biopsies: a comparison to stereological point counting.
Open this publication in new window or tab >>Semiquantitative evaluation overestimates the degree of steatosis in liver biopsies: a comparison to stereological point counting.
2005 (English)In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 18, no 7, 912-916 p.Article in journal (Refereed) Published
Abstract [en]

The degree of steatosis in liver biopsies is usually assessed by a morphological semiquantitative approach in which the histopathologist uses a four-graded scale: 0-3 or none, slight, moderate and severe. Scores 1-3 are considered to correspond to fat deposition in <33, 33-66 and >66% of the hepatocytes. There is a considerable inter- and intra-individual variation in such scoring methods and a more standardized and quantitative approach is preferable. In the present study, we compare the semiquantitative technique with the stereological point counting method in the assessment of hepatic steatosis. A total of 75 archived liver needle biopsies were used. They were selected according to the original routine diagnosis of slight, moderate or severe steatosis. In all, 10 randomly selected images from each biopsy were digitized into a computer, a point grid lattice was superimposed and the number of hits on fat globules was counted. A pathologist scored the specimens in a four-graded scale as described above. The mean liver biopsy area (volume) with fat in hepatocytes was 2.2% for grade 1, 9.2% for grade 2 and 23.1% for grade 3. The kappa value for the semiquantitative estimates was 0.71 for the unweigthed kappa and 0.87 for weighted kappa. The intraclass correlation coefficient (ICC) was 0.99 for images counted twice and 0.95 when two sets of images were captured from the same biopsy. These ICCs indicate excellent agreement and above that of the semiquantitative estimates. In conclusion, the area/volume of fat content of the hepatocytes is greatly overemphasized in semiquantitative estimation. Furthermore, the point counting technique has a better reproducibility than visual evaluation and should be preferred in estimates of liver steatosis in scientific studies and in clinical contexts when the amount of steatosis is important for treatment and prognosis, such as liver transplantation.

Keyword
Liver, quantification, steatosis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17322 (URN)10.1038/modpathol.3800370 (DOI)15920560 (PubMedID)
Available from: 2009-03-18 Created: 2009-03-18 Last updated: 2017-12-13Bibliographically approved
2. Long-term follow-up of patients with NAFLD and elevated liver enzymes.
Open this publication in new window or tab >>Long-term follow-up of patients with NAFLD and elevated liver enzymes.
Show others...
2006 (English)In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 44, no 4, 865-873 p.Article in journal (Refereed) Published
Abstract [en]

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver enzymes in patients of developed countries. We determined the long-term clinical and histological courses of such patients. In a cohort study, 129 consecutively enrolled patients diagnosed with biopsy-proven NAFLD were reevaluated. Survival and causes of death were compared with a matched reference population. Living NAFLD patients were offered repeat liver biopsy and clinical and biochemical investigation. Mean follow-up (SD) was 13.7 (1.3) years. Mortality was not increased in patients with steatosis. Survival of patients with nonalcoholic steatohepatitis (NASH) was reduced (P = .01). These subjects more often died from cardiovascular (P = .04) and liver-related (P = .04) causes. Seven patients (5.4%) developed end-stage liver disease, including 3 patients with hepatocellular carcinoma. The absence of periportal fibrosis at baseline had a negative predictive value of 100% in predicting liver-related complications. At follow-up, 69 of 88 patients had diabetes or impaired glucose tolerance. Progression of liver fibrosis occurred in 41%. These subjects more often had a weight gain exceeding 5 kg (P = .02), they were more insulin resistant (P = .04), and they exhibited more pronounced hepatic fatty infiltration (P = .03) at follow-up. In conclusion, NAFLD with elevated liver enzymes is associated with a clinically significant risk of developing end-stage liver disease. Survival is lower in patients with NASH. Most NAFLD patients will develop diabetes or impaired glucose tolerance in the long term. Progression of liver fibrosis is associated with more pronounced insulin resistance and significant weight gain.

Keyword
Liver, quantification, steatosis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17323 (URN)10.1002/hep.21327 (DOI)17006923 (PubMedID)
Available from: 2009-03-18 Created: 2009-03-18 Last updated: 2017-12-13Bibliographically approved
3. Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study.
Open this publication in new window or tab >>Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study.
Show others...
2007 (English)In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 47, no 1, 135-141 p.Article in journal (Refereed) Published
Abstract [en]

Background/Aims: The effect of statins on hepatic histology in non-alcoholic fatty liver disease (NAFLD) is not known. This study explores hepatic histology in NAFLD patients before and after initiation of statin therapy and compares histological outcome with NAFLD patients who had not been prescribed statins.

Methods: Sixty-eight NAFLD patients were re-evaluated. Follow-up ranged from 10.3 to 16.3 years. Subjects were clinically investigated and a repeat liver biopsy was obtained. No patient was taking statins at baseline while 17 patients were treated with statins at follow-up.

Results: At baseline, patients that later were prescribed statins had significantly higher BMI and more pronounced hepatic steatosis. At follow-up patients on medication with statins continued to have significantly higher BMI. Diabetes was significantly more common among patients on medication with statins and they had significantly more pronounced insulin resistance. However, they exhibited a significant reduction of liver steatosis at follow-up as opposed to patients not taking statins. Despite exhibiting a high risk profile for progression of liver fibrosis, only four patients on statin treatment progressed in fibrosis stage.

Conclusions: Statins can be prescribed in patients with elevated liver enzymes because of NAFLD.

Keyword
Non-alcoholic fatty liver disease, Histology, Statin, Metabolic syndrome
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17324 (URN)10.1016/j.jhep.2007.02.013 (DOI)17400325 (PubMedID)
Available from: 2009-03-18 Created: 2009-03-18 Last updated: 2017-12-13Bibliographically approved
4. Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease
Open this publication in new window or tab >>Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease
Show others...
2009 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 44, no 3, 366-374 p.Article in journal (Refereed) Published
Abstract [en]

Objective: Moderate alcohol consumption has been reported to be inversely associated with cardiovascular disease and total mortality. The importance of non-alcoholic fatty liver disease (NAFLD) is increasing and many NAFLD patients suffer from cardiovascular disease. In these patients, moderate alcohol consumption could be beneficial. The aim of this study was to investigate whether low alcohol intake, consistent with the diagnosis of NAFLD, is associated with fibrosis progression in established NAFLD.

Material and methods: Seventy-one patients originally referred because of chronically elevated liver enzymes and diagnosed with biopsy-proven NAFLD were re-evaluated. A validated questionnaire combined with an oral interview was used to assess weekly alcohol consumption and the frequency of episodic drinking. Significant fibrosis progression in NAFLD was defined as progression of more than one fibrosis stage or development of endstage liver disease during follow-up.

Results: Mean follow-up (SD) was 13.8 (1.2) years between liver biopsies. At follow-up, 17 patients (24%) fulfilled the criteria for significant fibrosis progression. The proportion of patients reporting heavy episodic drinking at least once a month was higher among those with significant fibrosis progression (p=0.003) and a trend towards higher weekly alcohol consumption was also seen (p=0.061). In a multivariate binary logistic regression analysis, heavy episodic drinking (p0.001) and insulin resistance (p0.01) were independently associated with significant fibrosis progression.

Conclusions: Moderate alcohol consumption, consistent with the diagnosis of NAFLD to be set, is associated with fibrosis progression in NAFLD. These patients should be advised to refrain from heavy episodic drinking.

Keyword
Alcoholic liver disease, fatty liver, histopathology, liver fibrosis, non-alcoholic fatty liver disease
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17133 (URN)10.1080/00365520802555991 (DOI)
Available from: 2009-03-07 Created: 2009-03-07 Last updated: 2017-12-13Bibliographically approved
5. The clinical relevance of the Nonalcoholic Fatty Liver Disease Activity Score (NAS) in predicting fibrosis progression
Open this publication in new window or tab >>The clinical relevance of the Nonalcoholic Fatty Liver Disease Activity Score (NAS) in predicting fibrosis progression
Show others...
2008 (English)Article in journal (Other academic) Submitted
Abstract [en]

Objective: The NAFLD activity score (NAS) is a newly proposed system to grade the necroinflammatory activity in liver biopsies of NAFLD patients. This study evaluates the usefulness of the NAS in predicting clinical deterioration and fibrosis progression in NAFLD.

Methods: One hundred and twenty-nine patients with biopsy proven NAFLD were included in a long-term histological follow-up study. Clinical and histological course were compared between NASH, “borderline NASH”, and “not NASH” patients. Significant fibrosis progression in NAFLD was defined as progression of more than one fibrosis stage or development of end-stage liver disease during follow-up.

Results: Eighty-eight patients accepted re-evaluation and 68 underwent repeat liver biopsy. Mean time between biopsies was 13.8 ± 1.2 years (range 10.3-16.3). At baseline, NASH was diagnosed in 2 (1.6%) patients, and at follow-up, in 1 (1.5%) patient. A trend towards higher baseline NAS was seen in patients (n = 7) that developed end-stage liver disease (3.1 ± 0.9 vs. 2.4 ± 1.0; P = 0.062). Baseline NAS was significantly higher in patients with progressive fibrosis (2.9 ± 0.9 vs. 2.2 ± 0.9; P = 0.017), and NAS was independently associated with significant fibrosis progression tested in a multivariate analysis (P = 0.023). However, 18% of patients without NASH progressed significantly in fibrosis stage.

Conclusion: Although the NAS is independently associated with future risk of progressive fibrosis in NAFLD, the clinical usefulness of the score is limited due to the significant overlap in clinical development between NAS-score groups.

Keyword
Steatohepatitis, Fatty liver, Fibrosis progression, Clinical follow-up, Histopathology
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17325 (URN)
Available from: 2009-03-18 Created: 2009-03-18 Last updated: 2009-08-17Bibliographically approved

Open Access in DiVA

fulltext(1335 kB)6054 downloads
File information
File name FULLTEXT01.pdfFile size 1335 kBChecksum SHA-512
a22d3fbdf328392b4e998851d6bee3d837b912b227e600542a82ac5acb3ece67d9368ebfc7fefc47ee25b70170e8c54acbc2aca24dec837f02de0f59f583d049
Type fulltextMimetype application/pdf
cover(161 kB)98 downloads
File information
File name COVER01.pdfFile size 161 kBChecksum SHA-512
4a0225ca56fc00039859c6400a751a4fabeb832f7a41a673fb74b25d5a101343d8222cc5e4d37630418b385efc0eb224def5094fd1a4f46b689ed015310cd4ad
Type coverMimetype application/pdf

Authority records BETA

Ekstedt, Mattias

Search in DiVA

By author/editor
Ekstedt, Mattias
By organisation
Gastroenterology and HepatologyFaculty of Health SciencesDepartment of Endocrinology and Gastroenterology
Gastroenterology and Hepatology

Search outside of DiVA

GoogleGoogle Scholar
Total: 6054 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 1665 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf