Splenic Influences on the Blood in Chronic Liver Disease

The Influence of the spleen on the blood has been assessed ina series of 187 consecutive patients with chronic liver disease.Patients were described as having ‘hypersplenism’if the white blood count and/or platelet count were below 4·0x10⁹and 100x10⁹/1 respectively at the time of biopsy diagnosis andon at least one subsequent occasion. Using this definition 17per cent of patients with alcoholic cirrhosis had hypersplenism,compared with 38 per cent with cryptogenic cirrhosis and 26per cent with active chronic hepatitis. Studies with ⁵¹Cr labelled autogenous erythrocytes in 36 ofthe patients with different types of chronic liver disease showedthat the spleen rarely caused anaemia either by excessive splenicpooling or splenic haemolysis. Further studies with ⁵¹Cr labelledplatelets in 20 other patients showed that the splenic plateletpool was usually considerably increased and the platelet lifespan reduced. Some patients showed excessive destruction ofplatelets in the spleen but none of these features consistentlyrelated to thrombocytopenia. Splenic enlargement per se did not cause expansion of the plasmavolume in chronic liver disease. Of a total of 17 patients who underwent surgical operationsfor reduction of portal pressure five had hyperspienism butin these the haematological state was not significantly improvedat one month. However, none of the survivors of these operationssubsequently developed hyperspienism. One patient with severehypersplenism who underwent simple splenectomy was cured ofleucopenia but not of thrombocytopenia.     

Erythrocyte aldehyde dehydrogenase activity in alcoholic subjects and its value as a marker for hepatic aldehyde dehydrogenase in subjects with and without liver disease

Erythrocyte aldehyde dehydrogenase activity was assayed in actively drinking alcoholics, patients with alcoholic liver disease who claimed to be abstaining, patients with non-alcoholic liver disorders and normal controls. Hepatic cytosolic aldehyde dehydrogenase was also assayed in the majority of the subjects. Actively drinking alcoholics had significantly lower erythrocyte aldehyde dehydrogenase activity than controls (P less than 0.01) but abstaining alcoholic liver disease and non-alcoholic liver disorder subjects did not. There was a significant correlation between erythrocyte and hepatic cytosolic aldehyde dehydrogenase activity in the control group (r = 0.94, P less than 0.05) but not in the other study groups.     

Sex Hormone Changes in Chronic Liver Disease: A Matched Study of Alcoholic versus Non-alcoholic Liver Disease

Men with liver disease are hypogonadal and feminished. Europeanworkers consider the liver disease itself to be the major factorbut American workers blame alcohal consumption. We studied sexualdysfunction and sex hormones in three matched groups of men;controls (n=22), those with alcoholic liver disease (n=21),and those with non-alcoholic liver disease (n=21). Men withalcoholic liver disease had maore sexual dysfunction. Testosteroneand androsastenedione concentrations were lower and oestradiaoland dehydroepiandrosterone sulphate levels were raised in theliver disease groups. The changes were greatest in the alcoholicliver disease group. In this, the first controlled study, liverdisease per se appeares to cause sexual dysfunction and sexhormone changes but these changes are amplified by ethanol.     

Inducing efficacy of ethanol on hepatic drug metabolizing enzymes in patients

In liver biopsy material of eighty-nine patients with suspected liver disease the drug-metabolizing function was investigated. The capacity of the liver to oxidatively metabolize drugs was assessed by determination of cytochrome P-450 dependent monooxygenase activity in vitro. The biotransformational function of these microsomal enzymes was tested with compounds representing the activity of oxidative drug metabolism (7-ethoxycoumarin, p-nitroanisol and cytochrome c). From the eight-nine patients sixty-one had various liver diseases not related to ethanol and twenty-eight abused ethanol. When both groups were matched for age, sex, smoking, treatment with sedatives, drugs and degree of liver damage the alcoholic group had significantly higher activities of 7-ethoxycoumarin O-deethylase (EOD: 76.9 +/- 31.1 pmol min-1 mg-1 protein, mean +/- SD) than the non-alcoholic liver disease group (42.7 +/- 14.1). The inducing effect of ethanol was most striking on the EOD activity, less for the O-demethylation of p-nitroanisol (PNA) and not present for the NADPH-cytochrome c reductase. The induced patients were analysed in detail to find out which factors were responsible for the observed scatter of enzyme activities within the alcoholic group. Alcoholics with fatty liver (n = 7) had the highest EOD activities (108.9 +/- 25.0), patients with alcoholic hepatitis (n = 10) had significantly less activity (66.0 +/- 1.9) than the former group. However, alcoholics without liver damage (n = 6) had activities not significantly different (46.0 +/- 15.8) from controls (39.4 +/- 9.1). These subgroups among the alcoholics were comparable in terms of sex, age, smoking and drinking habits.(ABSTRACT TRUNCATED AT 250 WORDS)     

酒精性肝病患者血清TGF-β、IL-6和IL-8水平及临床意义

目的探讨酒精性肝病患者血清转化生长因子（transforming growth factor-β,TGF-β）白细胞介素-6（inter-leukin-6,IL-6）和白细胞介素-8（interleukin-8,IL-8）在酒精性肝病中的作用。方法 60例酒精性肝病患者按酒精性脂肪肝（n=20）、酒精性肝炎（n=20）和酒精性肝硬化（n=20）分为3组。采用ELISA法检测20例健康对照组和60例各类酒精性肝病患者血清中TGF-β、IL-6和IL-8水平。结果血清TGF-β、IL-6和IL-8水平随着肝脏病变程度加重而递增,酒精性脂肪肝组、酒精性肝炎组和酒精性肝硬化组3项指标水平均高于正常对照组,差异显著（P〈0.01）,其中以酒精性肝硬化组3项指标水平为最高。结论 TGF-β、IL-6和IL-8在酒精性肝病中具有重要作用,酒精性肝病患者血清TGF-β、IL-6和IL-8水平的检测可作为酒精性肝病病情监测和预后判断的有效指标。     

Intracranial and Cerebral Perfusion Pressure Changes Before, During and Immediately After Orthotopic Liver Transplantation for Fulminant Hepatic Failure

Several centres that perform liver transplantation for fulminanthepatic failure have experience of patients who have not regainedconsciousness despite adequate graft function. In some of these,decerebration because of elevation in intracranial pressurewas thought to have occurred intraoperatively or in the earlypost-operative period. In the present study six patients withfulminant hepatic failure who were transplanted had extraduralmonitors inserted before operation. Intracranial pressure had been controlled prior to transplanatationand rose during the preclamp phase of the operation. Levelsfell during the anhepatic phase but rose again during the reperfusionphase (p=0.033). Overall, from the induction of anaesthesiato the reperfusion phase there was a significant increase inmean intracranial pressure (p<0.01). The cerebral perfusionpressure fell after induction of anaesthesia from a median 54mmHg (range 46–62) to a median 35 mmHg (range 19–49,p<0.001) in the pre-clamp phase and remained low throughoutthe operation. During the first 10 hours after transplantation,three patients had further episodes of intracranial hypertensionrequiring treatment and it is important that monitoring shouldbe continued through this period.     

Not Wilson's disease: a review of misdiagnosed cases

During the period 1957–1987, 189 patients with neurologicalsigns and symptoms were referred to the Wilson's disease clinicat Addenbrooke's Hospital, Cambridge. The diagnosis was notconfirmed in 52 patients. Thirty-three of these 52 patientswere sent with a definite diagnosis of Wilson's disease, and12 had received chelation treatment. Ten patients were labelledas probable Wilson's disease; in nine cases no diagnosis hadbeen made but Wilson's disease was considered a possibilityrequiring exclusion. One patient only was mistakenly reportedto have Kayser-Fleischer rings. The presenting symptoms weretremor (n = 17), involuntary movements (n = 16), difficultyin walking (n = 12), personality changes (n=4) and epilepsy(n = 3). The mean delay in referral was 8 years (range 6 monthsto 20 years). Compared with the number of patients with confirmedneurological Wilson's disease seen in this period (137 patients)the referral diagnosis was correct in only 72% of cases. Thereasons for error, both clinical and biochemical, are discussed.     

Peri-operative decreased cAMP levels in long-term alcoholic patients

Long-term alcoholic patients have a five-fold higher risk of post-operative bleeding complications compared with nonalcoholic individuals. Serotonin increases and cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) decrease platelet aggregation. We examined the platelet-rich plasma levels of these substances and agonist-induced platelet aggregation in long-term alcoholic patients before and after surgery. Thirty-three consecutive patients (13 long-term alcoholics and 20 non-alcoholics) scheduled for tumour resections of the upper digestive tract were included in the study. The levels of cAMP were significantly decreased before and after surgery in long-term alcoholic patients, but there were no significant differences in cGMP and serotonin levels in alcoholic compared with non-alcoholic patients. In contrast to previous studies, no significantly altered aggregation responses in long-term alcoholics were found. A possible explanation is decreased inhibition through diminished cAMP levels; cGMP and serotonin do not seem to influence peri-operative haemostasis.     

Serum paraoxonase-1 in chronic alcoholics: relationship with liver disease

OBJECTIVES: To investigate the relationship between serum paraoxonase-1 and liver damage in chronic alcoholic patients. To assess the diagnostic accuracy of paraoxonase-1 plus standard biochemical tests in the assessment of liver damage in alcoholics. DESIGN AND METHODS: We studied 328 chronic alcoholics and 368 healthy individuals. RESULTS: Paraoxonase-1 activity was decreased and the concentration was increased in alcoholics (P<0.001). The enzyme activity was correlated with albumin (r=0.45; P<0.001) and prothrombin time (r=0.49; P<0.001). Addition of paraoxonase-1 activity measurement to a battery of biochemical tests increased the sensitivity in differentiating between patients and controls up to 96.6% but did not improve the sensitivity in differentiating between subgroups of alcoholics. CONCLUSIONS: Paraoxonase-1 was related to the severity of alcoholic liver disease. Its measurement was useful in discriminating between patients and healthy subjects, but did not add any valuable information in subgroups of alcoholics.     

The association between glycemic, lipids and blood pressure control among Israeli diabetic patients

Background: It is recommended that in diabetes mellitus patientsall risk factors for cardiovascular disease should be controlled. Aim: To evaluate the rate of reaching all glycemic, lipids andblood pressure target levels among diabetic patients in Israeland to analyze demographic and clinical parameters associatedwith it. Design: A cross-sectional study. Methods: The study was conducted in Maccabi Healthcare Services,Israel's second largest health maintenance organization. Allpatients (n = 41 936), older than 20 years, who were listedon Maccabi Healthcare Service's diabetes mellitus computerizeddatabase and had all three study parameters (HbA1c, LDL-C andblood pressure levels during 2005) were eligible for the study.The rate of reaching HbA1c <7.0%, LDL-C <100 mg/dl andblood pressure <130/85 mmHg, as well as its association withvarious demographic and clinical parameters were analyzed. Results: Only 13% of all study patients achieved all three targetlevels. The parameters which were significantly associated withgoal achievement were compliance to medical treatment for allthree parameters (OR 1.56, 95% CI 1.44–1.69, P = 0.0001),male gender (OR 1.42, 95% CI 1.31–1.54, P = 0.0001), comorbiditywith ischemic heart disease (OR 1.23, 95% CI 1.13–1.34,P = 0.0001), and >12 visits per year to family physician(OR 1.10, 95% CI 1.02–1.19, P = 0.012). Conclusion: Non-compliance with treatment and sub-optimal follow-upby family physicians are associated with increased risk of failureto control major risk factor among diabetic patients.     

Associated liver disease in alcoholic pancreatitis

Two studies investigating the association of liver disease with acute and chronic pancreatitis in alcoholics are presented. In a retrospective study of 50 patients, no clinical liver disease was found in 9 patients with acute pancreatitis, while 23 (56%) of 41 patients with chronic pancreatitis had liver disease by clinical criteria. Of this latter group, 8 were confirmed histologically; thus 19% of patients with chronic pancreatitis had biopsy-proven cirrhosis. Fifty alcoholic patients with pancreatitis were prospectively evaluated. All who had clinical evidence of liver disease were biopsied. No cases of liver disease were encountered in the 4 patients with acute pancreatitis. Although 28 (60%) cases of clinically diagnosed liver disease were present in 46 patients with chronic pancreatitis, only 20 of these seemed significant (cirrhosis, alcoholic hepatitis, severe fatty liver), for an incidence of 43%. Thus, clinically significant alcoholic liver disease occurs quite frequently in association with alcoholic pancreatitis. This association is meaningful in more effective management of these patients in general and in preoperative assessment of the risk of surgery in particular.     

Iron Overload, but not Treatment with Desferrioxamine Favours the Development of Septicemia in Patients on Maintenance Hemodialysis

During a 19-month period we determined the incidence of bacterialinfection among 39 patients treated with desferrioxamine whohad end-stage renal disease and were undergoing maintenancehemodialysis. Twenty-three received desferrioxamine becauseof aluminium-related bone disease, and 16 because of iron overload.A control group of 193 patients on maintenance hemodialysisbut without desferrioxamine was used. No difference was foundin the incidence of septicemia or of all bacterial infectionsbetween the patients with aluminium-related bone disease treatedwith desferrioxamine and the control patients (0.12 vs. 0.12septicemia per patient-therapy-year, p>0.05; 0.23 vs. 0.26bacterial infections per patient-therapy-year, p>0.05). Theincidence of septicemia in patients treated with desferrioxaminefor iron overload, however, was almost three times that in thecontrol patients (0.36 vs. 0.12 septicemia per patient-therapy-year,p<0.01). To assess the effect of iron overload itself, wedetermined the frequency of bacterial infection in patientson regular hemodialysis who have never received desferrioxamine.These were subdivided into three groups according to serum ferritinlevel which indicated normal or low iron stores (Group I: serumferritin 10-330 µg1/1, n=125), moderate (Group II: serumferritin 331-1000 µg/1, n=49) or more advanced iron overload(Group III: serum ferritin 1001-2000 µg/1, n=10). Comparedto patients with normal or low serum ferritin levels (GroupI), we found a significantly higher rate of bacterial infectionamong patients in Group II compared with Group I (0.18 vs. 0.34infections per patient-therapy-year, p<0.05) and Group IIIcompared with Group I (0.18 vs. 0.58 infections per patient-therapy-year,p<0.01). These results suggest that treatment with desferrioxaminedoes not favour the development of septicemia or bacterial infectionindependently of iron overload and that iron overload itselfmay predispose patients on regular hemodialysis to bacterialinfection.     

Free and total carnitine and acylcarnitine content of plasma, urine, liver and muscle of alcoholics

1. Plasma and urine free and total carnitine and acylcarnitine levels were assayed in 12 control subjects and 20 chronic alcoholics with fatty liver. Although the alcoholics had a wider range of values than the controls, there was no significant difference between the two groups. 2. Hepatic free and total carnitine and long- and short-chain acylcarnitines were assayed by a radioenzymatic method in samples from seven control subjects and seven alcoholics. No significant differences in any of the indices were noted between the patient and control groups and it was concluded that carnitine deficiency did not contribute to alcoholic fatty liver in patients without cirrhosis. 3. Skeletal muscle free and total carnitine and long- and short-chain acylcarnitines were assayed in eight alcoholics and seven control subjects. The alcoholics had significantly higher total and free carnitine levels. It is suggested that this reflects a selective enrichment of the biopsy sample with type I carnitine-rich fibres due to the type II fibre atrophy found in approximately half the patients.     

Cell-mediated immunity to acetaldehyde in alcoholic liver disease demonstrated by leukocyte migration test.

To determine whether a sensitization to ethanol metabolites occurs in alcoholic liver disease, reactivity of lymphocytes to nontoxic amounts of acetaldehyde was studied by direct elaboration of migration inhibitory factor (MIF) production. Eighteen alcoholics with various degrees of biopsy-proven liver damage showed increased MIF production in response to acetaldehyde; the mean value of the group differed significantly from 15 healthy controls, 15 subjects with nonalcoholic liver disease, and 15 alcoholics without liver involvement (P less than 0.001, P less than 0.001, P less than 0.02, respectively). Among the alcoholics with liver disease, none individuals (50%) with histological signs of advanced alcoholic hepatitis showed the highest percentage of inhibition of migration; the value differed significantly from the remaining patients with lesser degrees of hyaline necrosis in liver biopsies (P less than 0.005). These results indicate that acetaldehyde is involved in the pathogenesis of alcoholic hepatitis. Clinically, this test might facilitate the selection of patients with alcoholic hyaline necrosis.     

Biomarkers of alcohol consumption in patients classified according to the degree of liver disease severity

OBJECTIVE: In the search for optimal biomarkers of excessive drinking, only a few studies have been conducted to compare the relationships between ethanol consumption, liver status, and various laboratory markers of ethanol-induced diseases. MATERIAL AND METHODS: Concentrations of carbohydrate-deficient transferrin (%CDT and CDTect methods), serum sialic acid (SA), gamma-glutamyl transferase (gamma-GT), aspartate aminotransferase (ASAT), mean corpuscular volume (MCV), and a marker of fibrogenesis (PIIINP) were studied in 102 alcoholics with (n=59) or without (n=43) alcoholic liver disease. Controls were 34 healthy volunteers who were either social drinkers or abstainers. RESULTS: Although concentrations of all markers were significantly higher in the alcoholic patients than in the healthy controls, their diagnostic characteristics showed a considerable degree of variation. The %CDT, SA, and MCV showed the strongest correlations with the amount of recent alcohol intake. The presence of liver pathology notably influenced the results of CDTect, GT, ASAT, and PIIINP. In ROC analyses, the highest rates of diagnostic accuracy for detecting hazardous drinking were reached with GT (0.94), CDT (0.86), and SA (0.85), followed by MCV (0.79) and ASAT (0.77). Upon abstinence, the estimated times for normalization varied between 10 days (CDTect) and 25 days (GT). CONCLUSIONS: Our data suggest distinct differences in the clinical characteristics of biological markers of ethanol consumption. While the overall accuracy of CDT and GT appear to be highest in the detection of problem drinking, serum SA and PIIINP measurements are of further value when the effects of liver pathology and ethanol drinking need to be differentiated.     

Molecular adsorbent recirculating system dialysis in patients with acute liver failure who are assessed for liver transplantation

Objective To assess the usefulness of dialysis with the molecular adsorbent recirculating system (MARS) in patients with acute liver failure who fulfil criteria for liver transplantation.Design Observational cohort study.Setting ICU at a liver transplantation centre.Patients Twenty-two patients (23 episodes) received MARS dialysis. They were either listed for LT (n = 14), delayed (n = 1), or not listed (contra-indication, n = 7).Interventions A total of 56 MARS treatments (median per patient 2; mean duration 7.6 ± 2.6 h) were performed on haemodialysis.Measurements and results Clinical and biological variables were assessed before and 24 h after MARS therapy. The rate of recovery of liver function without transplantation was compared with an expected rate and survival was analysed.Following MARS dialysis, we observed an improvement in the grade of hepatic encephalopathy (P = 0.02) and the Glasgow coma score (P = 0.02), a decrease in conjugated bilirubin (P = 0.05) and INR (P = 0.006), and an increase in prothrombin index (P = 0.005). Overall, liver function improved in seven patients (32%): four listed patients in whom transplantation could be avoided and three patients among those not listed due to contra-indications. The transplant-free recovery rate in listed patients was 29% (vs. expected 9%, P = 0.036). Listed patients (n = 14) had a higher 30-day survival rate [86% (12/14) vs 38% (3/8), P = 0.05] and a higher long-term survival rate (P = 0.02).Conclusions A statistically significant improvement of liver function was observed after MARS therapy. Transplant-free recovery was more frequent than expected. The apparent benefit of MARS dialysis to treat acute liver failure needs to be confirmed by a controlled study.     

Antiendothelial cell antibodies in lupus: correlations with renal injury and circulating markers of endothelial damage

Systemic lupus erythematosus is characterized by the productionof a broad spectrum of autoantibodies. Autoantibodies directedagainst endothelial cells (AECA) have been particularly welldocumented. We investigated associations between such antibodies,double-stranded DNA (dsDNAb), phospholipid (cardiolipin, ACA),and indices of activity and chronicity scored on renal biopsyspecimens from 22 patients with acute lupus. AECA were presentin 73% of these patients, and both the percentage of patientswith AECA and the mean antibody titre fell significantly aspatients entered remission. When patients already on immunosuppressivetherapy were excluded from analysis (n = 7), only levels ofAECA and DNAb (p = 0.02) correlated with histological evidenceof active lesions and the presence of glomerular epithelialcell crescents; no correlation was found with chronic changesin the renal biopsies. Serum von Willebrand factor (vWf) andserum total protein S levels, two parameters reflecting endothelialcell function, were also measured during acute disease and remission.vWf concentrations were elevated during acute disease (m = 1.9lU/ml, p = 0.02), but the values did not correlate with AECAtitres. In contrast, total protein S levels were reduced (0.81lU/ml vs. 0.97 lU/ml, p = 0.01) during active disease, but remainedwithin the normal range (0.56–1.16 lU/ml). Furthermore,protein S levels were inversely related to levels of AECA (r= –0.4, p = 0.01). AECA were therefore present in mostpatients with acute lupus nephritis and were associated withhistological evidence of active renal injury and serologicalevidence of endothelial cell dysfunction. These data provideindirect support for a pathogenic role for AECA in lupus nephritis.     

Antiendothelial cell antibodies in lupus: correlations with renal injury and circulating markers of endothelial damage

Systemic lupus erythematosus is characterized by the productionof a broad spectrum of autoantibodies. Autoantibodies directedagainst endothelial cells (AECA) have been particularly welldocumented. We investigated associations between such antibodies,double-stranded DNA (dsDNAb), phospholipid (cardiolipin, ACA),and indices of activity and chronicity scored on renal biopsyspecimens from 22 patients with acute lupus. AECA were presentin 73% of these patients, and both the percentage of patientswith AECA and the mean antibody titre fell significantly aspatients entered remission. When patients already on immunosuppressivetherapy were excluded from analysis (n = 7), only levels ofAECA and DNAb (p = 0.02) correlated with histological evidenceof active lesions and the presence of glomerular epithelialcell crescents; no correlation was found with chronic changesin the renal biopsies. Serum von Willebrand factor (vWf) andserum total protein S levels, two parameters reflecting endothelialcell function, were also measured during acute disease and remission.vWf concentrations were elevated during acute disease (m = 1.9lU/ml, p = 0.02), but the values did not correlate with AECAtitres. In contrast, total protein S levels were reduced (0.81lU/ml vs. 0.97 lU/ml, p = 0.01) during active disease, but remainedwithin the normal range (0.56–1.16 lU/ml). Furthermore,protein S levels were inversely related to levels of AECA (r= –0.4, p = 0.01). AECA were therefore present in mostpatients with acute lupus nephritis and were associated withhistological evidence of active renal injury and serologicalevidence of endothelial cell dysfunction. These data provideindirect support for a pathogenic role for AECA in lupus nephritis.