Ulrik Mathiesen

Long-term follow-up of patients with NAFLD and elevated liver enzymes.

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. (HEPATOLOGY 2006;44:865–873.)

Increased liver echogenicity at ultrasound examination reflects degree of steatosis but not of fibrosis in asymptomatic patients with mild/moderate abnormalities of liver transaminases.

AIMS To investigate whether hyperechogenicity of liver can reliably be interpreted as liver steatosis and if any concomitant or isolated fibrosis can be disclosed. PATIENTS AND METHODS A series of 165 patients with no signs or symptoms of liver disease referred because of slightly to moderately raised aminotransferases (alanine aminotransferase and/or aspartate aminotransferase 0.7-5.0 microkat/l) for more than 6 months were prospectively investigated with a comprehensive laboratory profile, ultrasound examination of liver and percutaneous liver biopsy Fibrosis was assessed quantitatively and according to Metavir. Steatosis was graded as none, mild, moderate or severe. RESULTS Of 98 (59.4%) patients with raised echogenicity, 85 (86.7%) had liver steatosis of at least moderate degree, 9 patients with same degree of steatosis had normal echogenicity and 13 patients with no or only mild steatosis had a hyperechogenic liver (sensitivity 0.90, specificity 0.82, positive predictive value 0.87, negative predictive value 0.87). About the same relations were found regardless of body mass index and degree of fibrosis. With increased echogenicity together with high attenuation (n = 591 and reduced portal vessel wall distinction (n = 79), positive predictive value increased to 0.93 and 0.94, respectively. Quantitatively assessed fibrosis (mean +/- SD) was 3.2 +/- 4.6% of biopsy area with normal and 2.3 +/- 1.8% with raised echogenicity (ns). Echogenicity was normal in 5 out of 9 patients with septal fibrosis and in 4 out of 6 patients with cirrhosis. Any structural, non-homogenous findings at ultrasound were not associated with architectural fibrotic changes and none had nodular contours of liver surface. CONCLUSIONS Assessment of liver echogenicity is of value for detection or exclusion of moderate to pronounced fatty infiltration (correct classification 86.6%) but cannot be relied upon in diagnosing fibrosis, not even cirrhosis in asymptomatic patients with mild to moderately elevated liver transaminases.

The Clinical Significance of Slightly to Moderately Increased Liver Transaminase Values in Asymptomatic Patients

The clinical significance of slightly to moderately increased liver transaminase values in asymptomatic patients.

Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease.

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 (p<0.001) and insulin resistance (p<0.01) 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.

Low clinical relevance of the nonalcoholic fatty liver disease activity score (NAS) in predicting fibrosis progression

Abstract Background/Aims. The nonalcoholic fatty liver disease (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 course and change in fibrosis stage were compared between nonalcoholic steatohepatitis (NASH), “borderline NASH,” and “not NASH” patients. Significant fibrosis progression 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 reevaluation 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 toward higher baseline NAS was seen in patients (n = 7) who developed end-stage liver disease (3.1 ± 0.9 vs. 2.2 ± 1.0; p = 0.050). Baseline NAS was associated with progressive disease in a univariate binary logistic regression analysis (p = 0.024), but no difference was seen in the multivariate analysis including the NAS, portal inflammation, and perisinusoidal fibrosis. Moreover, 18% of patients without NASH progressed significantly in fibrosis stage. Conclusions. The ability of the NAS to predict progression of NAFLD is poor. The clinical usefulness of the score is limited due to the significant overlap in clinical development between NAS score groups. To use the NAS as endpoint in treatment trial is not justified.

A statistically rule-based decision support system for the management of patients with suspected liver disease

The paper describes how a decision support system in liver diseases, mostly oriented to prediction of the necessity for liver biopsy, has been developed. The system designed is a hybrid one and consists of two parts: logical and statistical. The logical part contains rules, formulated on the basis of current medical knowledge, which enables recognition of clear cases; diseased or non-diseased. The unclear cases are classified on the basis of rules statistically extracted from databases. These rules have been reached after a comprehensive exploratory analysis of the sample of 165 patients with slightly to moderately raised levels of routine liver tests but without signs or symptoms of liver diseases. The extracted decision diagrams which simulate traditional medical diagnosis conduct have been found to be superior to discriminant analysis and probabilistic inductive learning. They use only a limited number of laboratory tests to detect the necessity for biopsy.

Design and delivery of information resources and knowledge bases for the diagnosis and management of liver disorders

The paper presents how a design and implementation of a system for the investigation of patients suffering from liver disorders were done. The system is developed on the Apple Macintosh using the Hypercard system. Hypercard is a general purpose application development tool based on the hypertext technique. The system consists of a collection of chunks of text (medical knowledge, patient management procedure, statistical rules etc.) linked appropriately. The emphasis is on allowing the users to get access to the information they needed. The contents of the system are text and active links. By simple navigation commands-such as merely clicking a mouse button, the users are allowed to move around in the information base and get hold of the information sought.<<ETX>>