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PubMed2026

Revealing the Shared Genetic Architecture of Metabolic Dysfunction-Associated Steatotic Liver Disease-Related Traits Through Genomic Structural Equation Modeling.

Although individual traits related to metabolic dysfunction-associated steatotic liver disease (MASLD) have been investigated through large-scale genome-wide association studies (GWASs), the shared genetic susceptibility across these traits remains unclear. We therefore conducted a multivariate GWAS of key MASLD-related traits to elucidate their common genetic architecture. We applied genomic structural equation modeling to model a latent genetic factor (MASLD-F) underlying genetically correlated MASLD-related traits, leveraging their GWAS-derived genetic correlations. We then performed functional annotations, including fine-mapping, transcriptome-wide association study, and cell- and tissue-type-specific enrichment analyses, and conducted Mendelian randomization analyses to identify modifiable risk factors. Our multivariate MASLD-F GWAS identified 50 independent variants across 48 genomic loci. Transcriptomic imputation identified several MASLD-F-associated genes, including ARNTL, NPC1, BTBD10, VDAC2, TSKU, SFMBT1, and ABHD17C. We observed significant enrichment of MASLD-F-related genetic signals predominantly in brain tissues, pancreatic islets, and the adrenal gland. Additionally, six modifiable risk factors and four modifiable protective factors for MASLD-F were identified. These findings reveal a complex shared genetic architecture underlying MASLD components, thereby expanding our understanding of disease pathogenesis and providing novel insights for precision medicine and public health interventions.

Humans↗
PubMed1998

Quantitative studies of testicular atrophy following portacaval shunt in rats.

To evaluate the differential effects of portacaval shunting (PCS) on the morphological changes that occur in humans with portal-systemic encephalopathy, male rats underwent either PCS (13) or sham operations (10). Normal adult rats (6) were used as controls. All animals were killed 5 to 7 weeks after the surgery. The wet weight of the testes was obtained. Hematoxylin-eosin (HE)-stained sections at 5-micrometers thickness were used for stereological analysis using an image analysis system. Apoptosis was assessed quantitatively in HE and in in situ end-labeling (ISEL)-stained slides, while mitotic activity and mast cell numbers were assessed in 20 high-power fields. There was a significant reduction in the testicular mass (664 mg) in PCS rats in comparison with sham (2,199 mg) and control (1,937 mg) rats (P <.00001). The thickness of germinal epithelium was significantly reduced in PCS rats (64 micrometers) compared with sham (126 micrometers) and control groups (108 micrometers). The number of tubules per square millimeter and the mean curvature were significantly increased in PCS rats (P <.00001). There was a 112-fold increase in apoptosis in PCS rats (112) in comparison with the control and sham-operation groups (1.2 and 0.7, respectively). Mitosis was significantly reduced in the PCS group (P =.0089), but mast cells were unchanged. The results suggest that PCS in the absence of liver dysfunction produces testicular atrophy by reduction in mitosis, maturation arrest, and increased apoptosis of the germinal epithelium. PCS may therefore be responsible for gonadal atrophy that occurs with advanced liver disease in humans.

Animals↗
PubMed2006

Successful treatment with etanercept in a patient with hepatotoxicity closely related to infliximab.

To date, hepatotoxicity with anti-TNF therapy has been associated with concomitant liver-toxicity drugs, infection or malignant diseases. We report the case of one patient with spondyloarthropathty who presented severe liver dysfunction related to infliximab. After the second infusion serum controls showed an slightly increase of transaminases. Before the administration of fifth infusion, infliximab therapy was stopped due to severe liver damage (AST 327 mU/ml, ALT 656 mU/mL, GGT 140 mU/mL, alkaline phosphate 227 mU/mL). Ten weeks after infliximab discontinuation serum concentrations of liver blood tests were normal but ankylosing spondylitis symptoms had relapsed. Therefore, he was treated with etanercept with a rapid and sustained improvement. Serum concentrations of albumin, AST, ALT, GGT and alkaline phosphate were followed and did not change for five months.

Antibodies, Monoclonal↗
PubMed1992

Role of liver allograft biopsy in patient management.

Acute rejection is the end result of progressive accumulation (most prominently in portal tracts) of mononuclear cells, PMNs, and eosinophils. The anatomic location of these cells, such as outside the limiting plate, in the venous endothelium or biliary epithelium, appears to change with the development of acute rejection. Although neither the density of the mononuclear cell infiltrate nor the total number of mononuclear cells and PMNs appear to correlate closely with the syndrome of acute rejection, spillout from the portal tracts and the number of eosinophils are reliable predictors of acute rejection in our population of patients. Acute rejection is a syndrome and liver dysfunction is an essential part of the diagnosis. The transient appearance of portal tract pathologic changes consistent with acute rejection occurs without hepatic dysfunction in approximately 10 to 20% of patients. Although the nature of this apparently innocent phenomenon is not understood, resolution occurs without antirejection therapy. Because of the complexity of liver transplantation care, and the need to minimize immunosuppression, serial biopsy continues to supply dynamic information needed for allograft monitoring. We propose that the data safely obtained from these biopsies can guide immunosuppression therapy.

Biopsy, Needle↗
PubMedDate not supplied

Diffuse hepatic fibrosis in congenital cytomegalovirus infection.

Liver dysfunction in congenital cytomegalovirus (CMV) infection is common but usually self-limited. We describe a patient with congenital CMV infection that resulted in diffuse (noncirrhotic) hepatic fibrosis and liver failure. Morphologic patterns of liver disease in congenital CMV are briefly discussed.

Cytomegalovirus Infections↗
PubMed2004

Erectile dysfunction as a sentinel symptom of cardiovascular autonomic neuropathy in heavy drinkers.

Because autonomic neuropathy (AN) is not routinely assessed in chronic alcoholism, its features and relationship with other disease parameters remain undefined. The very existence of true alcohol-related autonomic dysfunction, in the absence of alcoholic hepatopathy, is even controversial. We aimed this study at evaluating the frequency and pattern of AN in a population of heavy drinkers without liver dysfunction. We also investigated the putative risk factors for AN as well as its relationship to peripheral neuropathy (PN). Autonomic function was evaluated in 70 detoxified alcoholics and 70 well-matched controls by heart-rate response to deep breathing, heart-rate response to standing from lying position, and blood pressure response to standing up. PN was assessed by electroneurography (ENG). Detailed information about sensorimotor and autonomic symptoms, nutritional status, and parameters reflecting alcohol intake were recorded. No patients showed signs of caloric/protein malnutrition. PN was found in 74% and AN (abnormal test results in two of three tests performed) in 26%; abnormalities in at least one autonomic test were found in 62%. All patients with PN were symptomatic, mainly due to sensory disturbances. In line with this, ENG abnormalities were more evident at sural nerves. AN was symptomatic in 10 of 18 patients, and its sole clinical expression was impotence: indeed, the pattern of autonomic involvement was mainly parasympathetic. AN did not correlate with PN, nor with any parameter reflecting the amount of alcohol intake; only performances on heart-rate response to standing from lying position were related to the duration of abuse. The lack of correlation between PN and AN may suggest a different pathophysiology for these two complications. Unlike PN, AN is often asymptomatic. Among symptomatic patients (55%), erectile dysfunction seems to be the sole symptom, in line with the higher degree of parasympathetic damage.

Adult↗
PubMed1998

Endogenous benzodiazepine-like compounds and diazepam binding inhibitor in serum of patients with liver cirrhosis with and without overt encephalopathy.

BACKGROUND/AIM: Despite some controversy, it has been suggested that endogenous benzodiazepine plays a role in the pathogenesis of hepatic encephalopathy. The aim of the present study was to evaluate the concentrations of endogenous benzodiazepines and the peptide, diazepam binding inhibitor, in the blood of patients with liver cirrhosis with and without overt encephalopathy, and to compare these levels with those of consumers of commercial benzodiazepines. SUBJECTS: Normal subjects (90), benzodiazepine consumers (14), and cirrhotic patients (113) were studied. METHODS: Endogenous benzodiazepines were measured by the radioligand binding technique after high performance liquid chromatography (HPLC) purification. The presence of diazepam and N-desmethyldiazepam was assayed by HPLC-electrospray tandem mass spectrometry. Diazepam binding inhibitor was studied in serum by radioimmunoassay. RESULTS: Endogenous benzodiazepines were below the limit of detection in 7% of patients with encephalopathy. When detectable, their levels were at least comparable with those of benzodiazepine consumers and correlated with the liver dysfunction but not the stage of encephalopathy. Serum levels of diazepam binding inhibitor tended to decrease when endogenous benzodiazepines levels increased. CONCLUSIONS: Endogenous benzodiazepines may accumulate in patients with liver cirrhosis during the course of the disease, and the phenomenon appears to be independent of the presence or absence of encephalopathy.

Aged↗
PubMed2006

[Systemic lupus erythematosus and nucleosome].

The property of nucleosome in systemic lupus erythematosus (SLE) is reviewed. Nucleosome, complex of histone and DNA, is thought to have a pivotal role in pathogenesis of SLE. It is formed during apoptosis that is increased in peripheral lymphocytes of SLE. The concentration of nucleosome is elevated in SLE, probably related with disease activity. Nucleosome is speculated that the clearance from peripheral blood is decreased and that is modified by viral infection to become more immunogenic. Anti-nucleosome antibody is highly positive in majority of SLE, and is very specific for SLE except scleroderma and mixed connective tissue disease. This antibody is thought as a diagnostic marker and probably an activity marker for SLE. Anti-nucleosome antibody forms immune complex with nucleosome. As histone has strong positive charge, it is demonstrated that this nucleosome/anti-nucleosome complex is bound to negatively charged heparan sulfate of glomerular basement membrane in kidney. Then, complements bind to this antibody to generate lupus glomerulonephritis. Although main site of apoptosis in SLE is considered as lymphocytes, we experienced a case with SLE who had liver dysfunction with elevated soluble Fas ligand (sFasL) and apoptosis in her hepatocytes in the active stage of SLE. We measured serum sFasL, and found the relation of sFasL and liver involvement in active SLE. As major source of nucleosome should be apoptosis of lymphocytes in SLE, hepatocytes could be another candidate of apoptosis in some SLE.

Antibodies, Antinuclear↗
PubMedDate not supplied

The use of TIPS in chronic liver disease.

The development of cirrhosis and portal hypertension in the natural history of chronic liver disease is associated with many complications. A transjugular intrahepatic portosystemic stent shunt (TIPS) is a metal prosthesis that has been shown to be very effective in lowering sinusoidal portal pressure, and therefore is effective in the management of complications of cirrhosis, especially those related to portal hypertensive bleeding and sodium and water retention. In patients with acute variceal bleeding not responding to pharmacologic and endoscopic treatments, a reduction of the hepatic venous pressure gradient to < 12 mmHg or by > 20% with TIPS has been shown to be effective in controlling the acute bleed and in preventing rebleeding. For stable patients whose acute variceal bleed is controlled, TIPS is equal to combined beta-blocker and band ligation in the prevention of recurrent variceal bleed. TIPS is also more effective than large volume paracentesis in the control of refractory ascites, and may confer a survival advantage over repeated large volume paracentesis. TIPS has also been used in the management of other complications related to portal hypertension including ectopic varices, hepatic hydrothorax, and hepatorenal syndrome with some success, but experience is still rather limited. Miscellaneous uses include treatment of Budd Chiari Syndrome, portal hypertensive gastropathy and hepatopulmonary syndrome. Careful patient selection is vital to a successful outcome, as patients with severe liver dysfunction tend to die post-TIPS despite a functioning shunt. All patients who require a TIPS for treatment of complications of cirrhosis should be referred for consideration of liver transplant.

Chronic Disease↗
PubMed1988

[Clinical observations of hepatic artery infusion therapy combined with hepatic artery ligation in metastatic liver cancers].

Twenty-five patients with liver metastases from advanced gastrointestinal cancers were treated by hepatic arterial infusion chemotherapy by insertion of a catheter into the hepatic artery. All patients also underwent ligation of the hepatic artery. The anticancer agents used were adriamycin 10-30 mg, mitomycin C 10-20 mg and 5-fluorouracil 250-500 mg. The effect was assessed according to the criteria for clinical evaluation of chemotherapy for solid cancers by Koyama and Saito. The response rate for partial response was 24.0% among all 25 patients, including 25.0% (2/8) for stomach cancer and 28.6% (4/14) for colorectal cancer. The survival time with palliative resection of the primary lesion was prolonged significantly (p less than 0.05) in comparison with no resection. As for the side effects of hepatic arterial infusion chemotherapy, bone marrow suppression was most frequently found in 80.0% of patients, followed by gastrointestinal symptoms in 68.0%. In addition, fever occurred in 20.0%, stomatitis in 20.0%, liver dysfunction in 16.0% and alopecia in 4.0%. However, the side effects were all controllable. As to hepatic artery ligation, there was no serious complication except for one case of liver abscess.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Severe yellow fever with 23-day survival.

In a severe case of jungle yellow fever, acquired in the Brazilian mid-west region, clinical and laboratory evidence of hepatic and renal failure, cardiovascular disturbance, coma and bleeding disorder developed. The patient was treated in an intensive care unit and hemodialysis was performed. In spite of severe liver dysfunction, most biochemical parameters returned to normal values but the patient finally died of respiratory failure on the 23rd day, due to secondary bacterial pneumonia. A post-mortem liver biopsy showed regeneration of normal liver architecture. Without the bacterial respiratory complication, the patient probably would have survived.

Adolescent↗
PubMedDate not supplied

Preoperative nutrition assessment in liver transplantation.

Nutrition assessment and therapy in end-stage liver disease has become increasingly important with the advent of orthotopic liver transplantation. Reduced lean body mass, increased risk of sepsis, and altered metabolism of carbohydrates, protein, and fat are characteristic of patients with liver dysfunction. This study assesses the prevalence of protein-calorie malnutrition and the relative utility of various parameters used to define protein-calorie malnutrition in 104 patients before liver transplantation. Five subgroups were identified for analysis: primary biliary cirrhosis (PBC, n = 21), sclerosing cholangitis (SC, n = 12), chronic active hepatitis (CAH,n = 34), acute hepatitis (AH,n = 11), and other liver diseases (OD,n = 26). Clinical characteristics, anthropometric measurements, secretory protein levels, 24-h urinary creatinine and urea nitrogen, and immunological studies were assessed. Significant differences between groups were noted in age, height, weight, and percentage ideal body weight (IBW), but no differences were noted with respect to triceps skin fold (TSF) and arm muscle circumference (AMC), where uniform depletion of fat and protein stores was found. Overall percentage IBW was significantly elevated (112 +/- 20, mean +/- SD, p < 0.001), whereas TSF and AMC percentage standards were 71 +/- 33 and 89 +/- 11% (respective p < 0.001). With the < 5th percentile of TSF and AMC as markers of malnutrition, 33 and 43% of patients were malnourished, respectively. Hepatic synthetic function was impaired in all groups, with overall albumin 25 +/- 0.6 g/L, transferrin 1.60 +/- 0.66 g/L, and prothrombin 16.8 +/- 6.2 s.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1998

Effect of rebamipide on liver damage and increased tumor necrosis factor in a rat model of endotoxin shock.

We investigated the effect of rebamipide, a novel antiinflammatory agent, on liver damage in a rat model of circulatory shock induced by bacterial endotoxin (E. coli lipopolysaccharide, LPS). Endotoxemia for 6 hr resulted in a 5.9-fold rise in the serum levels of nitrite (P < 0.05) with a significant rise in the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactic dehydrogenase (LDH), suggestive of liver dysfunction. The increased activities of serum ALT, AST, and LDH, but not serum nitrite were significantly inhibited by rebamipide (100 mg/kg, orally for five days). Myeloperoxidase activity in the liver was significantly elevated in the rats with endotoxemia by 2.4-fold (P < 0.05), which was also significantly inhibited by rebamipide. Upon LPS injection, serum TNF-alpha levels peaked at 1 hr after LPS (from 167.4 +/- 20.0 to 1570.0 +/- 100.0 pg/ml) and thereafter rapidly declined. The increased TNF-alpha level measured at 1 hr was significantly inhibited by pretreatment with rebamipide (100 mg/kg for five days). It is suggested that rebamipide exerts a strong protective effect on the LPS-induced liver damage through inhibition of activation of neutrophils and TNF-alpha production.

Alanine↗
PubMed2003

Cardiac dysfunction in portal hypertension among patients with cirrhosis and non-cirrhotic portal fibrosis.

BACKGROUND/AIMS: In cirrhosis, diastolic dysfunction of heart is well documented. Contribution of portal hypertension towards cardiac changes in cirrhosis is difficult to assess. We examined the patients of non-cirrhotic portal fibrosis who have portal hypertension without liver insufficiency to understand the contribution of portal hypertension in causing cardiac changes. METHODS: Cardiac function was studied in four groups of patients: normal controls, patients with non-cirrhotic portal fibrosis (having portal hypertension without liver dysfunction) and cirrhotics with and without ascites. Cardiac function was evaluated by echocardiography. Additional measurements of plasma renin activity and aldosterone levels were performed. RESULTS: Diastolic function as assessed by the ratio between E wave and A wave (E/A ratio), was significantly lower in patients with non-cirrhotic portal fibrosis (median 1.3) compared to normal controls (median 1.52). However, even lower values were observed in cirrhotics without ascites (median 1.05) and with ascites (median 0.94). There was a significant correlation (r=-0.75) between plasma aldosterone levels and the E/A ratio in cirrhotics. CONCLUSIONS: Diastolic dysfunction is not only present in cirrhosis but also in non-cirrhotic portal fibrosis. It indicates that portal hypertension is an important factor in the genesis of cardiac dysfunction.

Adult↗
PubMed2005

Cholesterol accumulation and liver cell death in mice with Niemann-Pick type C disease.

Niemann-Pick type C (NPC) disease develops as a result of mutations in the NPC1 gene that encodes a protein involved in the net movement of unesterified cholesterol from the late endosomal/lysosomal compartment to the metabolically active pool of sterol in the cytosol of virtually every cell in the body. Although early publications emphasized the neurodegeneration occurring in children with this mutation, more recent clinical information suggests that serious liver disease also is an important part of this syndrome. These studies, therefore, were undertaken to characterize the liver dysfunction seen in mice with this same mutation. The NPC mouse develops significant hepatomegaly that reaches 8% of body weight at 5 to 6 weeks of age. This increase in liver size is associated with a linear increase in cholesterol content and with accumulation of amorphous cellular inclusions in both hepatocytes and macrophages. During the few weeks after birth, significant elevation of the plasma alkaline phosphatase level occurs, as also is seen in the human infant with this disease. At 4 to 5 weeks of age, plasma aminotransferase levels also rise abruptly. Histologically, at this time there is apoptosis, but no excess deposition of collagen or glycogen. mRNA expression is elevated for caspase 1, caspase 6, and several enzymes associated with sterol biosynthesis and bile acid formation. In conclusion, the NPC mouse has liver disease similar to that seen in the NPC infant and represents a relevant model for exploring the molecular events occurring in this form of liver disease.

Alanine Transaminase↗
PubMed1990

Effects of intra-arterial chemotherapy with a new lipophilic anticancer agent, estradiol-chlorambucil (KM2210), dissolved in lipiodol on experimental liver tumor in rats.

Anticancer effects and biodistribution of a new lipophilic anticancer agent, estradiol-chlorambucil (KM2210), dissolved in lipiodol (LPD) were investigated as an intra-arterial chemotherapy (IAC) on Walker 256 carcinosarcoma grown in the liver of 136 Wistar rats. All rats treated with KM2210 (10 mg)-LPD survived for 90 days after administration, whereas none of the rats with LPD alone were alive for more than 19 days. Histological examination revealed that there was no viable tumor cell in the encapsulated necrotic tumor at 21 days after administration. There was no significant liver dysfunction or leukopenia due to KM2210. The biodistribution study using [14C, 3H]KM2210-LPD solution showed that KM2210 accumulated selectively in tumor and that the tumor-to-normal-liver and tumor-to-blood ratios were 10 and 1,000, respectively, at 21 days after administration. These results suggest that KM2210 has potential clinical application in the treatment of human liver cancer.

Animals↗
PubMed1983

Amyloid A fibril degrading activity in serum in liver disease--relation to serum acute phase and other protein levels.

Human serum contains amyloid A degrading activity. This activity is decreased in patients with reactive systemic amyloidosis. To study the specificity of this finding, we evaluated the effect of liver disease per se on the amyloid degrading activity in serum as well as its relation to serum amyloid A (SAA), the putative precursor of amyloid A fibrils, and other serum protein levels in alcoholic and non-alcoholic non-malignant liver diseases without signs of amyloidosis. The amyloid A-degrading activity was significantly decreased in liver cirrhosis. The lowest activity was seen in patients with advanced cirrhosis. There was a positive correlation between the degradative activity and indices of hepato-cellular synthetic function (serum albumin, r = 0.77; serum prealbumin, r = 0.65). Most of the patients with liver disease had a detectable SAA level; 77% had a level higher than 5 mg/l (compared to 12% among blood donors). However, the SAA increase was generally only slight, e.g. in alcoholic liver cirrhosis the median SAA level was 15 mg/l. The results show that liver dysfunction per se decreases amyloid A-degrading activity in serum. A reduced activity cannot therefore be regarded as specific for reactive amyloidosis. Since reactive amyloidosis is extremely rare in liver cirrhosis, it seems obvious that a reduced amyloid degrading activity alone, in the absence of a markedly elevated SAA level, does not predispose, at least in patients with liver disease, to amyloidosis.

Amyloid↗
PubMedDate not supplied

Sex hormones during alcohol withdrawal: a longitudinal study of 29 male alcoholics during detoxification.

It is a well-known fact that alcohol affects sex hormone levels in males. Even in the absence of liver dysfunction, there is still a direct toxic effect of ethanol on testosterone synthesis resulting in acutely decreased values. This study is based on 29 male alcoholics without severe signs of liver disease treated on the alcohol detoxification ward at Huddinge hospital in Stockholm, Sweden during 1995. The aim was to study levels of sex hormones in male alcoholics during detoxification with benzodiazepines and after 3 weeks of sobriety. Blood samples were taken three times: one day after admission (day 2) when the patient was sober, at discharge (day 5) and after 3 weeks of sobriety (day 21). Levels of testosterone and sex hormone-binding globulin (SHBG) showed the same pattern during detoxification and follow-up. They were both low, but generally within normal limits, on days 2 and 5, but raised after 3 weeks of sobriety. Follicle stimulating hormone (FSH) and luteinizing hormone (LH) were initially high, but were substantially depressed during detoxification. Levels of FSH recovered after 3 weeks, whereas LH remained at the same level. Most patients exhibited generally low levels of both FSH and LH, however. Levels of oestrone decreased steadily. There were no correlations between levels of sex hormones and the number of milligrams of oxazepam administered to the patients during detoxification either at admission, at discharge or at follow-up. In summary, the endocrinological response to alcohol intake is complex. This study suggests that the duration of endocrinological recovery after drinking is a quite long-lasting process, that different hormones need different times to recover and that the normal glandular-pituitary feed-back processes may be partly put out of order.

Alcoholism↗