Hans Glaumann

Decreased survival of subjects with elevated liver function tests during a 28‐year follow‐up

The long‐term survival of subjects with nonalcoholic fatty liver disease (NAFLD) in comparison with both individuals with elevated transaminases attributable to other causes and the general poulation is poorly characterized. This study was undertaken to determine the frequency of NAFLD in a cohort of subjects who underwent liver biopsy from 1980 to 1984 because of elevated liver enzymes, and to assess mortality among subjects with NAFLD in comparison with the general Swedish population. The 256 subjects (61% men) had a mean age of 45 ± 12 years at the inclusion. Liver biopsies were blindly scored for NAFLD and nonalcoholic steatohepatitis (NASH). Causes of death were ascertained from the national Swedish Cause of Death Registry. Fatty liver was detected in 143 of the 256 subjects, including 25 (10%) with alcoholic fatty liver disease and 118 (46%) exhibiting NAFLD. Of those, 51 (20%) were classified as NASH and 67 (26%) as nonalcoholic bland steatosis. Cirrhosis was present in 9% at inclusion. During the follow‐up period, 113 (44%) of the total population and 47 (40%) of the 118 subjects diagnosed with NAFLD died. Of the 113 deaths, 37 were of cardiovascular disease and 16 of liver diseases. Compared with the total Swedish population, adjusted for sex, age, and calendar period, subjects with NAFLD exhibited a 69% increased mortality (standardized mortality ratio [SMR] = 1.69; 95% confidence interval [CI], 1.24–2.25); subjects with bland steatosis, a 55% increase (SMR, 1.55; 95% CI, 0.98–2.32; P = 0.062); and subjects with NASH, 86% (SMR, 1.86; 95% CI, 1.19–2.76; P = 0.007). Conclusion: Patients with NASH are at increased risk of death compared with the general population. Liver disease is the third most common cause of death among patients with NAFLD. (HEPATOLOGY 2009.)

Liver Investigation in 149 Asymptomatic Patients with Moderately Elevated Activities of Serum: Aminotransferases

The accidental finding of raised levels of serum aminotransferase levels may lead to extensive investigations of the liver in apparently healthy people. To identify diagnostic groups and their need for investigations, we have evaluated the results of all investigative procedures carried out in 149 asymptomatic patients with persistently raised serum levels of aminotransferases. Fatty liver was found in 64%. These patients often had a high body weight. A high alcohol intake and diabetes mellitus were also noted. Chronic active or persistent hepatitis was found in 20% of the patients. Six per cent had cirrhosis, 4% had alpha 1-antitrypsin deficiency, and 3.5% had hemochromatosis. Apart from ferritin, alpha 1-antitrypsin, and markers for hepatitis B, blood tests were of little value for distinguishing among different diagnostic groups. This was the case also for the imaging procedures, and neither liver scintigraphy nor ultrasonography was a reliable source of diagnostic information. The results of our study indicate that diagnosis in this group of patients cannot be made without liver biopsy.

Drug metabolism in human liver in vitro: Establishment of a human liver bank

Marked species differences in xenobiotics metabolism in the liver seriously limit extrapolations from animals to man. Because access to human liver is limited and periodic, we have set up a human “liver bank” available for metabolic studies. The liver tissue is obtained shortly after circulatory arrest from cadaveric (cerebral infarction) kidney transplant donors. Postmortem changes are minimal. Subcellular liver fractions are prepared immediately and part of this is used directly for assay. Intact pieces and subcellular fractions are stored in different media at −80°. Each liver is characterized by light and electron microscopy. Several enzymes, including cytochromes P‐450 and b5, NADPH‐cytochrome c reductase, demethylation of aminopyrine and amitriptyline, epoxidation of carbamazepine, oxidation of acetaminophen, and benzo[a]pyrene, were tested with freshly prepared fractions so that each liver got a “drug metabolic profile.” This “test battery” was repeated after storing to evaluate the effect of storage. Our preparation technique gave a well‐preserved microsomal fraction with minimal contamination. In freshly prepared microsomes the following activities (levels) were observed: cytochrome P‐450, 0.13 to 0.73 nmole/mg protein; NADPH‐cytochrome c reductase, 70 to 426 nmole/mg protein; demethylation of aminopyrine, 0.9 to 4.1, and of amitriptyline, 0.11 to 0.92 nmole/mg protein; carbamazepine‐10,11 epoxidation, 0.03 to 0.46 nmole/mg protein; oxidation of acetaminophen, 0.48 to 2.11, and of benzo[a]pyrene, 0.04 to 0.11 nmole/mg protein · min. These values are generally higher than in the literature. Our storage conditions were efficient: most of the activities were well preserved during storage for at least 6 mo. When pairs of enzyme activities (levels) were plotted against each other with fresh tissue there was good correlation between some but not all activities.

Mechanisms of Intralysosomal Degradation with Special Reference to Autophagocytosis and Heterophagocytosis of Cell Organelles

Publisher Summary This chapter describes the mechanisms of intralysosomal degradation with a special reference to autophagocytosis and heterophagocytosis of cell organelles. Autophagy is the process of sequestration of intracellular components and their subsequent degradation by the lysosomes. The process of degradation is of fundamental importance in cell function because under steady-state conditions subcellular components are broken down and resynthesized many times during the life span of the cells. Autophagy contributes to the turnover of cell constituents during physiological cell conditions. Autophagy is induced by numerous treatments, conditions, or agents that cause cell dysfunction. Biological components from the extracellular space can also enter the lysosomal compartment and become degraded through the process of heterophagy. The chapter discusses an experimental model in which intracellular organelles are introduced into the lysosomal apparatus of Kupffer cells by means of heterophagy. The study of the heterophagic model has advantages over induced autophagy because the degradation of each membrane constituent or cell organelle can be separately studied. The heterophagy model is also useful to evaluate the capacity of lysosomes to degrade various membrane components in vivo .

Centrilobular expression of ethanol-inducible cytochrome P-450 (IIE1) in rat liver

Western blot analysis of digitonin eluates as well as immunohistochemical analysis revealed a 30-fold higher concentration of cytochrome P-450IIE1 in the centrilobular than in the periportal regions of the rat liver. Ethanol treatment caused a selective centrilobular induction of P-450IIE1, whereas phenobarbital induced P-450IIB1/2 in both liver lobule regions. The heterogeneous distribution pattern of P-450IIE1 was also observed in cells isolated from either region and correlated to the relative content of P-450IIE1 mRNA in the two cell types. The regiospecific expression and induction of P-450IIE1 may explain why several hepatotoxins, known to be metabolized by this isozyme, primarily damage the centrilobular region in the liver.

Long-term follow-up of chronic hepatitis C patients with sustained virological response to alpha-interferon

BACKGROUND/AIMS This study aimed to determine the long-term outcome of hepatitis C virus (HCV)-infected patients who respond to interferon treatment with clearance of serum HCV RNA. METHODS We performed a long-term biochemical, virological, and histological follow-up of all sustained virological responders, defined as those who became HCV RNA negative at follow-up 6 months after the end of treatment, from 3 controlled interferon trials performed in Sweden between 1988 and 1994. RESULTS At biochemical and virological long-term follow-up performed in 26 sustained virological responders 3.5-8.8 years (mean +/- SD, 5.4+/-1.6 years) after the end of IFN therapy, 22 patients (85%) had normal serum ALT levels, and 24 patients (92%) were HCV RNA negative in serum. Liver biopsies performed in 23 patients 2.1-8.7 years (mean +/- SD, 5.0+/-1.8 years) after end of treatment showed no or minimal inflammation, whereas mild and probably irreversible fibrosis was seen in a few patients. CONCLUSION In this well-defined material of sustained responders to IFN therapy, the long-term prognosis was excellent. Nearly all had a durable response, not only biochemically and virologically, but more importantly also histologically with normalisation or near normalisation of previous histological lesions.

Autophagy, heterophagy, microautophagy and crinophagy as the means for intracellular degradation.

SummaryIt is generally accepted that the lysosomal compartment plays an important role in the degradation of cellular components.In this communication we discuss various experimental models which have been used to study mechanisms of intralysosomal degradation and also discuss the evidence obtained in support of the following proposals:1.The autophagosomes can be isolated into high purity and are the subcellular locus of induced protein degradation.2.Different membrane components such as proteins and lipids are degraded at different rates inside the lysosomes. Intralysosomal hydrolysis is not the rate limiting step in degradation.3.Lysosomes take up soluble material in vitro by invagination and pinching off of their membranes (microautophagy).4.Secretory vesicles can degrade their secretory contents by fusing with the lysosomes.

Gallbladder disease in patients with primary sclerosing cholangitis

BACKGROUND/AIMS Gallbladder abnormalities may be part of the spectrum in primary sclerosing cholangitis (PSC). The aim of the present study was to evaluate the occurrence and prognostic importance of gallbladder abnormalities in patients with PSC. METHODS Presence of gallbladder abnormalities was assessed in 286 patients with PSC treated at the Liver Unit, Karolinska University Hospital, Huddinge, between 1970 and 2005. RESULTS One or more gallbladder abnormalities were found in 41% of the patients. Gallstones were found in 25% and cholecystitis in 25%. Cholecystitis among patients with extrahepatic involvement of PSC (30% (65/214)) was significantly higher than among those with intrahepatic involvement (9% (6/70)) (P<0.0001). A gallbladder mass lesion with a mean size of 21 (+/-9) mm (S.D.) was found in 18 (6%) patients, in 56% (10/18) of whom it constituted gallbladder carcinoma. In 9 patients without a gallbladder mass lesion, histological re-evaluation disclosed epithelial dysplasia of the gallbladder. CONCLUSIONS Gallbladder disease is common in patients with PSC. Dysplasia and carcinoma are commonly found in gallbladder epithelium, suggesting that regular examination of the gallbladder in PSC patients could be of value for early detection of a gallbladder mass lesion. Cholecystectomy is recommended when such a lesion is detected, regardless of its size.

Natural history and outcome in 32 Swedish patients with small duct primary sclerosing cholangitis (PSC)

BACKGROUND/AIMS This study aims at describing the natural history and outcome of small duct primary sclerosing cholangitis (PSC). METHODS Thirty-two patients with small duct PSC were studied. The average time taken for diagnosis was 69 (1-168) months. The median follow-up time was 63 (1-194) months. RESULTS All patients including one who underwent liver transplantation because of end-stage liver disease and hepatocellular carcinoma were alive at follow-up. None developed cholangiocarcinoma. In 27 patients repeated cholangiographic examinations were done after a median time of 72 (12-192) months from first ERCP. Four developed features of large duct PSC. CONCLUSIONS Small duct PSC rarely progresses to large bile duct PSC and it seems to have a benign course in most patients and no development of cholangiocarcinoma was found.

Studies on the synthesis and transport of albumin in microsomal subfractions from rat liver

Abstract Washing liver microsomes with alkaline Tris buffer and treatment with ultrasonication makes it possible to distinguish between three types of microsomal proteins: namely, adsorbed, membranous, and luminal proteins. Of the luminal proteins, albumin is the major component. The relative amount of albumin is higher in the smooth fractions, especially the smooth II microsomes, than in the rough counterpart. The data indicate that albumin is synthesized on ribosomes attached to membranes, rather than on free ribosomes, that it is transferred to the lumen of the rough endoplasmic reticulum, and that it is subsequently transported into the smooth endoplasmic reticulum. Both smooth I and smooth II microsomes participate in this process, indicating that they originate from intracellular membranes of parenchymatous liver cells. The cellular migration of albumin as well as the release of albumin into the blood occur independently of protein synthesis. Phenobarbital treatment of the rats in vivo stimulates the rate of [14C]leucine incorporation into membranous proteins and increases the number of microsomal membranes, but has little or no effect on the microsomal albumin content or its synthesis.