Precirrhotic Liver Research Articles

Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver.

Type 2 diabetes mellitus is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development1,2, and increased stiffness is known to promote HCC progression in cirrhotic conditions3,4. Type 2 diabetes mellitus is characterized by an accumulation of advanced glycation end-products (AGEs) in the ECM; however, how this affects HCC in non-cirrhotic conditions is unclear. Here we find that, in patients and animal models, AGEs promote changes in collagen architecture and enhance ECM viscoelasticity, with greater viscous dissipation and faster stress relaxation, but not changes in stiffness. High AGEs and viscoelasticity combined with oncogenic β-catenin signalling promote HCC induction, whereas inhibiting AGE production, reconstituting the AGE clearance receptor AGER1 or breaking AGE-mediated collagen cross-links reduces viscoelasticity and HCC growth. Matrix analysis and computational modelling demonstrate that lower interconnectivity of AGE-bundled collagen matrix, marked by shorter fibre length and greater heterogeneity, enhances viscoelasticity. Mechanistically, animal studies and 3D cell cultures show that enhanced viscoelasticity promotes HCC cell proliferation and invasion through an integrin-β1-tensin-1-YAP mechanotransductive pathway. These results reveal that AGE-mediated structural changes enhance ECM viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.

Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to non-alcoholic steatohepatitis

Obeticholic acid (OCA) is a first-in-class farnesoid X receptor agonist and antifibrotic agent in development for the treatment of pre-cirrhotic liver fibrosis due to non-alcoholic steatohepatitis (NASH). We aimed to validate the original 18-month liver biopsy analysis from the phase III REGENERATE trial of OCA for the treatment of NASH with a consensus panel analysis, provide additional histology data in a larger population, and evaluate safety from >8,000 total patient-years' exposure with nearly 1,000 participants receiving study drug for >4 years. Digitized whole-slide images were evaluated independently by panels of three pathologists using the NASH Clinical Research Network scoring system. Primary endpoints were (1) ≥1 stage improvement in fibrosis with no worsening of NASH or (2) NASH resolution with no worsening of fibrosis. Safety was assessed by laboratory values and adverse events. Prespecified efficacy analyses included 931 participants. The proportion of participants achieving a ≥1 stage improvement in fibrosis with no worsening of NASH was 22.4% for OCA 25mg vs. 9.6% for placebo (p <0.0001). More participants receiving OCA 25mg vs. placebo achieved NASH resolution with no worsening of fibrosis (6.5% vs. 3.5%, respectively; p=0.093). Histology data in a larger population of 1,607 participants supported these results. Safety data included 2,477 participants. The incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and deaths was not substantively different across treatment groups. Pruritus was the most common TEAE. Rates of adjudicated hepatic, renal, and cardiovascular events were low and similar across treatment groups. These results confirm the antifibrotic effect of OCA 25mg. OCA was generally well tolerated over long-term dosing. These data support a positive benefit:risk profile in patients with pre-cirrhotic liver fibrosis due to NASH. Patients with non-alcoholic steatohepatitis (NASH) often have liver scarring (fibrosis), which causes an increased risk of liver-related illness and death. Preventing progression of fibrosis to cirrhosis or reversing fibrosis are the main goals of drug development for NASH. In this clinical trial of obeticholic acid (OCA) in patients with NASH (REGENERATE), we reaffirmed our previous results demonstrating that OCA was superior to placebo in improving fibrosis using a more rigorous consensus panel analysis of liver biopsies taken at month 18. We also showed that OCA treatment resulted in dose-dependent reductions of serum liver biochemistries and liver stiffness measurements compared with placebo, even in participants in whom histologic fibrosis did not change at 18 months, providing evidence that the benefit of OCA extends beyond what is captured by the ordinal NASH CRN scoring system. OCA was well tolerated with a favorable safety profile supporting a positive benefit: risk profile in patients with pre-cirrhotic liver fibrosis due to NASH.

Optimized Systematic Review Tool: Application to Candidate Biomarkers for the Diagnosis of Hepatocellular Carcinoma.

This review aims to develop an appropriate review tool for systematically collating metabolites that are dysregulated in disease and applies the method to identify novel diagnostic biomarkers for hepatocellular carcinoma (HCC). Studies that analyzed metabolites in blood or urine samples where HCC was compared with comparison groups (healthy, precirrhotic liver disease, cirrhosis) were eligible. Tumor tissue was included to help differentiate primary and secondary biomarkers. Searches were conducted on Medline and EMBASE. A bespoke "risk of bias" tool for metabolomic studies was developed adjusting for analytic quality. Discriminant metabolites for each sample type were ranked using a weighted score accounting for the direction and extent of change and the risk of bias of the reporting publication. A total of 84 eligible studies were included in the review (54 blood, 9 urine, and 15 tissue), with six studying multiple sample types. High-ranking metabolites, based on their weighted score, comprised energy metabolites, bile acids, acylcarnitines, and lysophosphocholines. This new review tool addresses an unmet need for incorporating quality of study design and analysis to overcome the gaps in standardization of reporting of metabolomic data. Validation studies, standardized study designs, and publications meeting minimal reporting standards are crucial for advancing the field beyond exploratory studies.

Assessment of native liver fibrosis using ultrasound elastography and serological fibrosis indices in children with biliary atresia after the Kasai procedure

Validated non-invasive examinations are necessary to monitor liver fibrosis in children with biliary atresia (BA) after the Kasai procedure. To evaluate the diagnostic accuracy of two-dimensional shear wave elastography (2D-SWE), transient elastography (TE), and the serologic biomarkers of aspartate transaminase-to-platelet ratio index (APRI) and Fibrosis-4 (FIB-4) score for evaluating native liver fibrosis in children with BA. We retrospectively reviewed same-day 2D-SWE and TE liver stiffness (LS) measurements of 63 patients with BA who underwent the Kasai procedure. The APRI and FIB-4 score were computed. Hepatic fibrosis was categorized into three clinical categories based on the ultrasound (US) hepatic morphology and clinical manifestations of liver cirrhosis: I, pre-cirrhotic liver state (n = 15); II, US and/or clinical signs of liver cirrhosis with compensated liver function (n = 27); and III, liver cirrhosis with decompensated liver function (n = 21). We compared area under the receiver operating characteristic curve (AUC) data among 2D-SWE, TE, APRI, and FIB-4 score. Combined evaluation of serologic fibrosis indices and US elastography was conducted and AUCs of combinations were analyzed. 2D-SWE, TE, APRI, and FIB-4 score showed good to excellent diagnostic accuracy for differentiating clinical categories (AUCs 0.779-0.955). AUC values were significantly increased after adding TE to FIB-4 score for detecting liver cirrhosis (P = 0.02). 2D-SWE, TE, APRI, and FIB-4 score are accurate non-invasive markers for monitoring native liver fibrosis in patients with BA. Combined use of serologic markers and US elastography could yield more accurate diagnoses of liver fibrosis than serologic markers alone.

Fatty Liver Disease and Hepatocellular Carcinoma: The Pathologist's View.

Chronic alcohol misuse and progressed nonalcoholic fatty liver disease (NAFLD) due to the metabolic syndrome and resulting to nonalcoholic steatohepatitis (NASH) are prime causes of hepatocellular carcinoma (HCC) in Western industrialized countries. The incidence of HCC in NASH-cirrhosis is lower than that of HCC occuring in HCV-related or alcoholic cirrhosis. Up to 20% of cases of alcohol-associated HCC may develop in pre-cirrhotic liver while HCC is also increasingly recognised in pre-cirrhotic NASH raising questions on appropriate surveillance measures for these patient populations. The recently described steatohepatitic subtype of HCC presents with higher frequency in NAFLD compared to alcoholic liver disease (ALD) patients. This review will mainly focus on histopathology and summarize current data on the epidemiology, pathogenesis, diagnosis and management of NAFLD- and ALD-related HCC.

Expression of hnRNPK & Claudin-4 in HCV-Induced Early HCC and Adjacent Liver Tissue.

BACKGROUND:HCC in Egypt usually occurs in HCV cirrhotic livers with poor prognosis due to late diagnosis. High hnRNPK & low Claudin-4 profiles indicate Epithelial Mesenchymal Transition (EMT), malignant transformation and high-grade tumours.AIM:We studied the immunohistochemical expression of hnRNPK and Claudin-4 in HCV induced early HCC (eHCC) and adjacent liver tissue in Egyptian patients to improve eHCC detection in cirrhotic livers with better curative therapy options.METHOD:We studied the immunohistochemical expression of hnRNPK and Claudin-4 in 100 Egyptian patients resection specimens of HCV induced early HCC (eHCC) and adjacent liver tissue, in order to improve eHCC detection in cirrhotic livers, thus improving their therapeutic options.RESULTS:Early HCC grade significantly directly correlated with nuclear hnRNPK/5HPFs count and inversely correlated with Claudin-4 expression %, with a converse correlation between hnRNPK and Claudin-4. Moreover in eHCC, combined hnRNPK ≥ 30/5HPFs & Claudin-4 ≥ 40% significantly distinguished low grade eHCC (G1) from high grade eHCC (G2&G3), with sensitivity 97% & specificity 69.7% for hnRNPK ≥ 30/5HPFs, and with sensitivity 70% & specificity 94.3% for Claudin-4 ≥ 40%. Moreover in the adjacent liver, both markers expressions significantly directly correlated with each other and with METAVIR fibrosis score but not with activity. Furthermore, 58% of eHCCs showed hnRNPK ≥ 30 Claudin-4 < 40% profile, indicating EMT type 3, compared to 26% with hnRNPK ≥ 30 Claudin-4 ≤ 10% profile in adjacent cirrhotic/ precirrhotic liver, with significant use of combined hnRNPK ≥ 30/5HPFs & Claudin 4 ≤ 10% as eHCC prediction cut offs in cirrhosis (p < 0.05).CONCLUSION:Combination of hnRNPK and Claudin-4 can indicate early HCC development in HCV cirrhotic livers using hnRNPK ≥ 30/5HPFs & Claudin-4 ≤ 10% cut offs. Also, combination of hnRNPK ≥ 30/5HPFs & Claudin-4 ≥ 40% can distinguish low grade eHCC (G1) from high grade eHCC (G2&G3).

Can Computerized Brain Training Games be Used to Identify Early Cognitive Impairment in Cirrhosis?

We evaluated whether commercially available, computerized "brain-training" games can be used to identify subtle cognitive impairments in patients with cirrhosis. We compared patients with cirrhosis who did not have overt encephalopathy (n=31), patients with pre-cirrhotic chronic liver disease (n=28), and normal controls without liver disease (n=16) with respect to their scores on the number connection test-A (NCT-A), the Inhibitory Control Test (ICT), and five, short (∼2.5 min), brain-training games that were administered on an Apple iPad and tested different cognitive domains. Patients with cirrhosis had similar scores to patients with pre-cirrhotic liver disease and slightly worse scores than normal controls in the NCT-A and the ICT, although these differences were not statistically significant. In contrast, patients with cirrhosis had significantly worse scores than patients with pre-cirrhotic liver disease and even more so than normal controls in all five of the brain-training games. After adjustment for age and educational attainment, these differences remained significant for two of the tests, "Color Match" which is a version of the Stroop test and measures selective attention, and "Memory Matrix", which measures visuospatial memory. The area under the receiver operating characteristic curve discriminating cirrhosis from pre-cirrhotic liver disease was 0.56 (95% confidence interval (CI) 0.41-0.72) for the ICT and 0.58 (95% CI 0.43-0.73) for the NCT-A, indicating no discrimination, while it was 0.75 (95% CI 0.63-0.87) for "Color Match" and 0.77 (95% CI 0.64-0.90) for "Memory Matrix", indicating good discrimination. Short, brain-training games administered on an iPad can be used as psychometric tests to detect subtle cognitive impairments in patients with cirrhosis without overt encephalopathy that could not be detected by the NCT-A or the ICT.

Computed tomography findings in liver fibrosis and cirrhosis

Computed tomography (CT) is inferior to the fibroscan and laboratory testing in the noninvasive diagnosis of liver fibrosis. On the other hand, CT is a frequently used diagnostic tool in modern medicine. The auxiliary finding of clinically occult liver fibrosis in CT scans could result in an earlier diagnosis. The aim of this study was to analyse quantifiable direct signs of liver remodelling in CT scans to depict liver fibrosis in a precirrhotic stage. Retrospective review of 148 abdominal CT scans (80 liver cirrhosis, 35 precirrhotic fibrosis and 33 control patients). Fibrosis and cirrhosis were histologically proven. The diameters of the three main hepatic veins were measured 1-2 cm before their aperture into the inferior caval vein. The width of the caudate and the right hepatic lobe were divided, and measured horizontally at the level of the first bifurcation of the right portal vein in axial planes (caudate-right-lobe ratio). A combination of both (sum of liver vein diameters divided by the caudate-right lobe ratio) was defined as the ld/crl ratio. These metrics were analysed for the detection of liver fibrosis and cirrhosis. An ld/crl-r <24 showed a sensitivity of 83% and a specificity of 76% for precirrhotic liver fibrosis. Liver cirrhosis could be detected with a sensitivity of 88% and a specificity of 82% if ld/crl-r <20. An ld/crl-r <24 justifies laboratory testing and a fibroscan. This could bring forward the diagnosis and patients would profit from early treatment in a potentially reversible stage of disease.

Mucosal Addressin Cell Adhesion Molecule (MAdCAM-1) Expression Is Upregulated in the Cirrhotic Liver and Immunolocalises to the Peribiliary Plexus and Lymphoid Aggregates

Enhanced cell expression of MAdCAM-1 is critical in tissue recruitment of lymphocytes in response to stimuli expressing the α4β7 integrin. MAdCAM-1 is well characterized in gut mucosa with emerging evidence of hepatic expression. (i) Compare quantitative/semi-quantitatively MAdCAM-1 expression in relation to early and advanced liver diseases (ii) Define the fine structure of vascular plexuses/lymphatics in the portal tract on which MAdCAM-1 is expressed. Using alkaline phosphatase anti-alkaline phosphatase methodology on paraffin embedded tissue sections (n=28) from cirrhotic individuals who underwent orthotopic liver transplant, we evaluated MAdCAM-1 expression and compared with pre-cirrhotic, fulminant hepatitis B, and non-cirrhotic portal hypertension tissue sections. The positive controls included normal colon tissue with negative controls without primary antibody and isotype-matched purified IgG. We developed a real time PCR to quantify levels of MAdCAM-1 mRNA in our samples. MAdCAM-1 was expressed in 27/28 of the cirrhotic sections, localized primarily to septal areas within (i) endothelium of the peribiliary vascular plexus (PBP) (ii) lymphoid aggregates, with absence from normal, non-cirrhotic portal hypertension and pre-cirrhotic livers. There was significant upregulation of MAdCAM-1 mRNA in cirrhosis (p<0.011), consistent with immunohistochemical analysis. MAdCAM-1 is up-regulated in cirrhosis with expression on PBP and lymphoid aggregates. MAdCAM-1 is likely to contribute to the localization and recruitment of α4β7 lymphocytes during the pathogenesis of cirrhosis. MAdCAM-1 could be a useful marker of advanced liver disease. Further studies with respect to the expression of MAdCAM-1 in the presence of reversible and non-reversible stages of liver disease may be of merit.

Intrahepatic cholangiocarcinomas in cirrhosis are hypervascular in comparison with those in normal livers

Intrahepatic cholangiocarcinomas (ICCs) are usually adenocarcinomas with fibrotic and hypovascular stroma. Intrahepatic cholangiocarcinomas in cirrhosis and precirrhotic liver (ICC-cirrhosis) are increasingly being diagnosed, and can display hypervascular enhancement resembling a hepatocellular carcinoma on dynamic imaging. In this study using ICC-cirrhosis (71 cases), ICC with non-specific reactive changes (ICC-reactive) (72 cases) and the cholangiocarcinoma component of combined hepatocellular cholangiocarcinoma (HCC-ICC) (30 cases), we tried to compare the tumour vasculature. It was found that ICC-cirrhosis and the cholangiocarcinoma component of HCC-ICC showed a higher density of arteries and microvessels (1.59 ± 0.58/mm(2) (mean ± SD) and 140 ± 43/mm(2) in ICC-cirrhosis and 1.74 ± 0.67/mm(2) and 131 ± 46/mm(2) in the cholangiocarcinoma component of HCC-ICC) than in ICC-reactive (1.26 ± 0.61/mm(2) and 103 ± 45/mm(2) ). Dynamic computed tomography (CT) and magnetic resonance imaging (MRI) showed that a majority of ICC-cirrhosis displayed strong hypervascular enhancement, whereas one-third of ICC-reactive each showed strong, weak and no or minimal enhancement respectively. The increased vascular density was positively correlated with enhanced arterial phase of dynamic CT and MRI. The density of arteries and microvessels of ICC-cirrhosis was higher than that in ICC-reactive and comparable to that in the cholangiocarcinoma component of HCC-ICC, and the higher density of arteries and microvessels in ICC may be responsible for the hypervascular enhancement of ICC-cirrhosis.

Indications for therapy in hepatitis B #

Increased treatment options that are more efficacious and safe and new knowledge on the natural history of chronic hepatitis B virus (HBV) infection have expanded the indications for therapy in hepatitis B. The question is no longer "Who should be treated?" but "When should treatment be initiated?" Treatment is clearly indicated in patients with life-threatening liver disease (acute liver failure, decompensated cirrhosis, or severe hepatitis flare) and in those with compensated cirrhosis and high levels of serum HBV DNA. For patients with precirrhotic liver disease, treatment indications should be based on clinical, biochemical, or histological evidence of liver disease, such as elevated alanine aminotransferase (ALT) levels, abnormal histology, and high levels of serum HBV DNA. The cutoff for ALT and HBV DNA values are constantly being revised and should be set at a lower level for older patients who may have been infected for a longer period of time. High serum HBV DNA levels persisting for a few decades are associated with increased risk of clinical outcomes, but there is insufficient data to support the initiation of treatment based on high serum HBV DNA alone, particularly in young patients, those with persistently normal ALT levels, and those with a single high HBV DNA level. The decision to initiate treatment at the time of assessment or to defer treatment should take into consideration other factors such as desire to start a family, occupational requirement, family history of hepatocellular carcinoma, access to care and insurance coverage, and commitment to long-term treatment and medication compliance. All patients who are not initiated on treatment should continue to be monitored so treatment can be started if and when the indication arises.

Hyperplastic foci in chronic liver disease: their proliferative activity assessed by nucleolar organizing region.

In the cirrhotic and precirrhotic liver, there may be small foci with increased cellularity and amphophilic cytoplasm. These are microscopic lesions that do not form macroscopically detectable nodules, which differ from the macroscopically apparent nodules of dysplastic nodules. In the present study, we assessed the proliferating activity of 12 hyperplastic foci in 11 patients with cirrhosis or chronic hepatitis, by staining for agyrophilic nucleolar organizing regions (AgNOR). The mean AgNOR count per nucleus in the hyperplastic foci ranged from 0.96 to 1.36 (mean, 1.13; SD 0.12), and from 0.81 to 1.06 (mean, 0.94; SD 0.08) in the controls. The AgNOR count in the hyperplastic foci was significantly higher than that in the controls (P < 0.01). Small hyperplastic foci show increased proliferative activity. Further study on these foci is required to clarify their relation to hepatocarcinogenesis.

種々の合併症にて術後不幸な転帰を辿った舌癌症例

General complications are sometimes associated with the treatment of head and neck tumor. We review a case of fatal tongue cancer with multiple complications.A 57-year-old female complained of tongue swelling. Sh e had a 5 × 3 × 2 cm well differentiated squamous cell carcinoma (T3N2M0) on the right side of the tongue. Complications before treatment included diabetes mellitus, a pre-cirrhotic liver and renal dysfunction. We performed surgery after chemotherapy by intraarterial injection.Following surgery, she developed fatal complications; severe hypoalb u minemia, lung edema, severe Pseudomonas aeruginosa infection, septic shock, disseminated intravascular coagulation (DIC) and peritonitis cartinomatosa. Twenty-four days after surgery, she died of multiple organ failure. Paying attention to pre-, intra-, and postoperative general conditions while treating head and neck malignancies is important.

Disappearance of hepatic parenchymal nerves in human liver cirrhosis.

The normal human liver receives a substantial autonomic innervation that is thought to subserve motor, metabolic, and sensory functions. In this study an antibody to a neural axoplasmic protein (PGP 9.5) was used to visualise autonomic nerves in tissue from normal, precirrhotic, and cirrhotic livers. Nerve fibres were readily identified in the parenchyma and portal tracts of normal livers, and in those where the histological diagnosis was non-specific reactive hepatitis or acute liver injury. In precirrhotic and cirrhotic livers nerves in portal tracts and fibrous septae remained prominent, but the parenchymal innervation was reduced in precirrhotic livers and was absent from regenerating nodules in established cirrhosis. The causes and functional consequences of this parenchymal denervation in cirrhosis remain to be established.

Biochemical changes in the rat after chronic thioacetamide intoxication

Male Wistar rats were given drinking water ad libitum with 0.075% thioacetamide (TAA) for 4 weeks. TAA treatment did not affect serum aminotransferase activities and total bilirubin content. The activities of 5′-nucleotidase, K +, Na +- and Mg 2+-adenosine triphosphatases in liver plasma membrane preparations were strongly depressed, while that of γ-glutamyl transferase was considerably increased. A decline in liver microsomal cytochrome P-450 and cytochrome b 5 concentrations was also recorded. In contrast, the content of reduced glutathione in liver homogenate supernatant (9000 g) increased about 2-fold. As plasma membrane associated enzymes seem to be exclusively affected, the liver plasma membrane could be involved in the pathogenesis of the TAA-induced precirrhotic liver changes.

Type III procollagen peptide and PZ-peptidase serum levels in pre-cirrhotic liver diseases

To obtain a dynamic and non-invasive picture of hepatic fibrosis in pre-cirrhotic liver diseases we measured both the concentration of the N-terminal peptide of procollagen III, as a marker of collagen synthesis, and the activity of PZ-peptidase, an enzyme involved in collagen degradation, in the serum of alcoholic or chronic viral hepatitis patients. Peptide serum levels were similar in chronic persistent hepatitis and controls, but significantly higher in chronic active hepatitis. Chronic persistent hepatitis patients had PZ-peptidase levels higher than controls, but similar to chronic active hepatitis. The increase in collagen synthesis without a parallel increase in collagen degradation seen in chronic active hepatitis could be regarded as a sign of impending cirrhosis, whereas the unbalanced rise in PZ-peptidase observed in chronic persistent hepatitis is consistent with the non-progressive character of this disorder. In alcoholic hepatitis both peptide concentration and PZ-peptidase activity were elevated, thus suggesting that both collagen synthesis and degradation are activated. However, the greater increase in PZ-peptidase than in peptide serum levels seen in some patients seems to indicate a minor tendency to progressive fibrosis or a trend towards resolution. Unlike liver disease patients, normal peptide and PZ-peptidase levels were found in patients with pancreatic fibrosis. Since circulating inhibitors and activators of the PZ-peptidase activity can be excluded, as proved by this study, joint peptide and PZ-peptidase serum measurements would seem to offer a simple reliable non-invasive method for differentiating and monitoring progressive and non-progressive forms of hepatic fibrosis.

Lysosomal enzymes in plasma, liver and spleen from rats with carbon tetrachloride-induced liver cirrhosis.

Plasma levels of the lysosomal enzymes, beta-hexosaminidase and beta-glucuronidase, were analyzed in rats with carbon tetrachloride induced liver cirrhosis. Out of 22 animals, 15 showed cirrhotic and 4 pre-cirrhotic livers. 4 cirrhotic animals exhibited cholestatic features with increased bilirubin, alkaline phosphatase (ALP) and aspartate aminotransferase (ASAT) in plasma. The remaining 15 pre-cirrhotic and cirrhotic rats showed clear significant changes only in ASAT levels. These 15 rats showed no consistent increase in plasma, spleen or liver lysosomal enzyme activities, whereas the 4 rats with cholestatic features exhibited considerable increases of lysosomal enzymes. The increased activities might be attributed to decreased biliary excretion and/or increased production of lysosomal enzymes by activated macrophages.

Severity of alcohol dependence in patients with alcoholic liver disease.

To determine the severity of dependence on alcohol in patients with alcoholic liver disease the severity of alcohol dependence questionnaire was administered to 193 patients with various types of alcoholic liver disease established histologically, in whom a detailed history of lifetime alcohol consumption was also obtained. Only 34 patients (18%) were classified as being severely dependent compared with 56% of patients without overt liver disease who were attending a neighbouring alcohol treatment unit. There was a significant correlation between the severity of dependence and mean daily alcohol consumption (r = 0.45 and 0.39 for men and women, respectively) but not duration of drinking. Dependence scores tended to be lower in patients with cirrhosis than in those with precirrhotic liver disease, but this difference reached significance only in women. These findings confirm that patients who develop chronic alcoholic liver disease are usually only mildly dependent on alcohol and support the hypothesis that patients who escape florid symptoms of alcohol dependence are at greater risk of developing liver damage because they are able to sustain a continual consumption of alcohol over many years.

Tumors of the liver: Pathologic features

Primary tumors of the liver infrequently develop in patients with a normal liver or in those who have not been exposed to one of several tumor-producing compounds. Hepatocellular adenoma was one of the rarest liver tumors prior to the use of oral contraceptives (OCs). Now the annual incidence in longterm users is estimated at 3-4/100,000. An adenoma that follows OC use is one that often regresses with discontinuation. Focal nodular hyperplasia is a nonencapsulated solitary lesion that has a fibrotic stellate center in which large thick-walled arteries are the source of the blood supply, and occurs most often in women during the menstrual age, and there is no evidence that OCs have increased their frequency. Adenomatous hyperplasia occurs occasionally in patients with submassive necrosis and also in those with cirrhosis. Liver cysts present most often in middle aged women and the ratio of females to males is 4:1. In the US, metastatic carcinoma of the liver is some 18-20 times more frequent and about 85% of these arise in a cirrhotic or precirrhotic liver. Malignant mesenchymal tumors have been associated with exposure to vinyl chloride of injection of Thorotrast. Signs and symptoms of liver disease occur in about 50% of patients with hepatic metastases with hepatomegaly being the most common physical sign. Metastatic carcinoma most often produces multiple umbilicated nodules that involve the liver uniformly. Portal hypertension may be associated with a hepatic neoplasm.

Macrocytosis in alcohol-related liver disease: its value for screening

The incidence of macrocytosis, defined as a mean corpuscular volume (MCV) of greater than 95 fl and large red cells on peripheral blood film, was determined in 303 alcoholics with liver disease (95 females: 208 males), 60 non-alcoholics with chronic liver disease (44 females: 16 males) and 35 control subjects (15 females: 20 males). Macrocytosis was found in 70.3% (213/303) of alcoholics with liver disease and in 23.3% (14/60) of non-alcoholics with liver disease, P less than 0.001. MCV values greater than 100 fl were seen in 49.5% (150/303) of alcoholics, but in only 3.3% (2/60) of non-alcoholics, P less than 0.001. Macrocytosis was more frequent in female, 86.3% (82/95) than in male alcoholics 63.0% (131/208), P less than 0.001. Serum folate values less than 3 microgram/l were found in 14.5% (44/303) of alcoholics and in 11.7% (7/60) of non-alcoholics. Low serum folate values were found in 18.3% (39/213) of alcoholics with macrocytosis and in 35.9% (28/78) of those with macrocytic anaemia. Twenty alcoholics with pre-cirrhotic liver disease were followed over three months. Macrocytosis was present in 85.0% (17/20) at the outset and in 40% (8/20) 3 months later. The changes in MCV were independent of alcohol intake and serum folate values. Macrocytosis is a useful diagnostic indicator of alcoholism. MCV values greater than 100 fl in patients with liver disease almost invariably indicate alcohol-related disease. In the short-term, changes in MCV are of little use in monitoring alcohol intake.