Biopsy-proven Liver Disease Research Articles

Diagnostic accuracy of point shear wave elastography in the detection of portal hypertension in pediatric patients.

The purpose of this study was to determine the usefulness of point shear wave elastography (p-SWE) of the liver and spleen for the detection of portal hypertension in pediatric patients. The study consisted of 38 healthy children and 56 pediatric patients with biopsy-proven liver disease who underwent splenic and liver p-SWE. The diagnostic performance of p-SWE in detecting clinically significant portal hypertension was assessed using receiver operating characteristic (ROC) curves. Reliable measurements of splenic and liver stiffness with p-SWE were obtained in 76/94 (81%) and 80/94 patients (85%), respectively. The splenic stiffness was highest in the portal hypertension group (P<0.01). At ROC curve analysis, the area under the curve in the detection of portal hypertension was lower for splenic p-SWE than for liver p-SWE (0.906 vs. 0.746; P=0.0239). The cut-off value of splenic p-SWE for portal hypertension was 3.14m/s, with a specificity of 98.59% and a sensitivity of 68.18%. The cut-off value of liver p-SWE for portal hypertension was 2.09m/s, with a specificity of 80.28% and a sensitivity of 77.27%. In pediatric patients, p-SWE is a reliable method for detecting portal hypertension. However, splenic p-SWE is less accurate than liver p-SWE for the diagnosis of portal hypertension.

Histological parameters and alcohol abstinence determine long-term prognosis in patients with alcoholic liver disease

Few data exist on predictors of long-term prognosis in patients with alcoholic liver disease (ALD). Most studies have only assessed short-term prognosis in patients with advanced ALD. We aimed to assess the prognostic impact of clinical, biochemical and histological parameters on long-term prognosis in patients with early/compensated and decompensated ALD. Consecutive patients (n=192) with biopsy-proven liver disease due to alcohol abuse were analyzed retrospectively. Prognostic factors were evaluated in patients with early/compensated ALD (n=60) and in patients with decompensated ALD (clinical decompensation and/or bilirubin >3mg/dl at entry) (n=132). Factors that predict long-term survival were identified using Cox regression models. Liver-related mortality at 5years was 13% in early/compensated and 43% in decompensated ALD. In early/compensated ALD patients, long-term prognosis was determined by fibrosis stage, but not by clinical or biochemical variables. Severe fibrosis (F3/4) was present in 52% and had a major impact on 10-year mortality (F3/4: 45% vs. F0-2: 0%, p<0.001). In contrast, in decompensated patients, a combination of clinical features (sex), biochemical markers of liver failure (bilirubin, international normalized ratio [INR]), and histological features (pericellular fibrosis) predicted long-term survival. During follow-up, abstinence from alcohol was an important predictor of survival in both early/compensated and decompensated ALD. Fibrosis stage is the main predictor of long-term survival in patients with early/compensated ALD, while clinical, biochemical and histological parameters predict survival in patients with decompensated disease. Promoting abstinence may improve survival in patients with both early and advanced ALD. In this study, we evaluated long-term outcome in 192 patients with alcoholic liver disease who underwent liver biopsy: 60 patients with early disease (no symptoms) and 132 patients with advanced disease (jaundice, complications of cirrhosis). Importantly, half of the patients with 'early' disease already had severe fibrosis or cirrhosis on liver histology and dismal outcome (45% mortality at 10years). Abstinence from alcohol improved the prognosis in both early and advanced stages of the disease.

Transient elastography for the detection of hepatic fibrosis in HIV-monoinfected adults with elevated aminotransferases on antiretroviral therapy.

Vibration-controlled transient elastography (VCTE) is increasingly used to assess liver fibrosis in viral hepatitis and fatty liver disease populations. Because the accuracy of VCTE in HIV-monoinfected populations has not been established, we evaluated its performance in assessing liver fibrosis in a cohort of HIV-monoinfected adults undergoing liver biopsy as part of a recently published clinical trial. HIV-infected adults with elevated aminotransferase levels for at least 6 months while receiving antiretroviral therapy, and without chronic viral hepatitis or other known causes of liver disease, were prospectively evaluated by VCTE, other noninvasive markers of fibrosis, and percutaneous liver biopsy as part of a cross-sectional study examining liver pathology. Sixty-six patients were evaluated by VCTE and liver biopsy. The cohort was in the majority male (92%), with a median age of 50 years (range 17-68). Biopsy identified bridging fibrosis in 14 (21%) and nonalcoholic steatohepatitis in 38 (58%) participants. VCTE was unsuccessful or unreliable in seven participants (11%). In the 59 participants with reliable results, median liver stiffness measurement (LSM) was 5.9 kPa (range 3.3-29.2 kPa); 25 participants (42%) had a LSM above 7.1 kPa, a value consistent with increased liver stiffness in other populations. VCTE had good sensitivity and specificity with an area under the receiver-operating characteristic curve (AUROC) of 93% for detection of moderate fibrosis (Ishak F ≥ 2; 95% confidence interval 86-99%). In HIV-monoinfected adults with biopsy-proven liver disease, LSM by VCTE was the best noninvasive predictor of fibrosis. Our findings support the continued use of VCTE for fibrosis screening in HIV-monoinfected patients with elevated aminotransferases.

Outcomes of transcatheter aortic valve replacement in patients with chronic liver disease.

Transcatheter aortic valve replacement (TAVR) has emerged as an alternative to high-risk surgery in patients with comorbid conditions. The role of TAVR in patients with liver disease has not been examined. We examined the procedural and intermediate to long-term follow-up outcomes of patients with severe symptomatic aortic valve stenosis and chronic liver disease, identified by liver biopsy or from a combination of clinical findings. All patients were treated with balloon-expandable transfemoral (TF) or transapical (TA) TAVR between November 2007 and February 2014. A total of 17 of 706 (2.41%) patients treated at our institution with TF [n=14] or TA [n=3] TAVR had chronic liver disease (mean age 77.65±9.06 years, 7 women, mean STS score 8.37, mean Charlson score 5.00, mean MELD score 11.35, Child-Turcotte-Pugh (CTP) Class A [n=11], B [n=6], C [n=0], biopsy proven liver disease [n=5]). Median follow-up was 466 days (range=12-1,403 days). The mean post-procedure length of hospital stay was 5.88±3.08 days. Procedural success was achieved in all cases. In-hospital mortality was 5.88% and 90-day mortality was 17.65%. Safety and efficacy endpoints as defined by the valve academic research consortium (VARC) were significant for one perioperative death from a proximate cardiac cause (post-operative day 14), one death after hospital discharge of unknown cause (post-operative day 12), two late deaths from non-cardiac causes (post-operative days 50 and 487, respectively), and one late death of unknown cause (post-operative day 1,005). There were no life-threatening or major bleeding complications. One patient had an MI, one had a transient ischemic attack, four had transient, Stage I, acute kidney injury and one had transient, Stage II, acute kidney injury. TF and TA TAVR are feasible methods for treating aortic stenosis in patients with chronic liver disease. In patients with mild to moderate chronic liver disease there are acceptable rates of early and late complications, however, outcomes in patients with advanced liver disease (MELD>20 or CTP class C) warrant further study.

Tissue inhibitor of metalloproteinase is increased in the serum of precirrhotic and cirrhotic alcoholic patients and can serve as a marker of fibrosis

One of the contributory factors to the development of cirrhosis is a decrease in collagenase activity, which may be related to levels of inhibitors such as serum tissue inhibitor of metalloproteinase. We therefore measured serum tissue inhibitor of metalloproteinase and serum procollagen III peptides (another proposed marker of fibrosis) in 16 healthy controls and 44 alcoholic patients with biopsy-proved liver disease, namely steatosis without fibrosis (n = 13), perivenular fibrosis (n = 10), septal fibrosis or cirrhosis or both (n = 15) and alcoholic hepatitis (n = 6). In alcoholic patients, serum tissue inhibitor of metalloproteinase values strongly correlated with fibrosis (rs = 0.70, p < 0.001). Compared with values in controls (177 +/- 12 ng/ml), serum tissue inhibitor of metalloproteinase was significantly elevated in perivenular fibrosis (330 +/- 22 ng/ml, p < 0.05), in septal fibrosis, cirrhosis or both (406 +/- 29 ng/ml, p < 0.001) and in alcoholic hepatitis (526 +/- 140 ng/ml, p < 0.001) but not in steatosis (204 +/- 17 ng/ml). In contrast, procollagen III peptides were significantly increased only in the septal fibrosis-cirrhosis group but not in the perivenular fibrosis group. With the threshold defined as the upper value of the steatosis group (resulting in a specificity of 100%), we found that serum tissue inhibitor of metalloproteinase was elevated in 50% of patients with perivenular fibrosis, in 87% of subjects with extensive fibrosis (septal fibrosis, cirrhosis or both) and in 67% of individuals with alcoholic hepatitis. The overall sensitivity of serum tissue inhibitor of metalloproteinase for detecting either perivenular fibrosis or more extensive fibrosis was 71%.(ABSTRACT TRUNCATED AT 250 WORDS)

MEASUREMENT OF CARBOHYDRATE-DEFICIENT TRANSFERRIN BY ISOELECTRIC FOCUSING/WESTERN

At present, the most reliable marker of recent and heavy alcohol intake is carbohydrate-deficient transferrin (CDT). While most CDT quantitation methods (including immunofixation and micro anion-exchange chromatography [MAEC] combined with radioimmunoassay [RIA]) either lack the precision required for diagnostic usage or are not commercially available, we recently described an isoelectric focusing/Western blotting (IEF/WB) procedure that provides sensitive and specific assessment of serum CDT content. However, a modified MAEC/RIA kit, supposedly more reliable than the original, is also being advanced as suitable for widespread clinical application. Therefore, we compared this modified MAEC/RIA procedure to the IEF/WB method of CDT quantitation in the following 108 subjects; 53 alcoholics undergoing detoxification without clinical or histological evidence of liver disease, 24 recently drinking alcoholics with biopsy-proven liver disease, eight alcoholics abstinent for more than 30 days with biopsy-proven liver disease, seven non-drinking patients with non-alcoholic liver disease, and 16 healthy controls. Although CDT measurements by the two methods were correlated (r = 0.60, P < 0.01), serum CDT values obtained with IEF/WB were nearly five-fold higher than those obtained with MAEC/RIA (e.g. 140.0 +/- 58 versus 28.5 +/- 16 mg/l among the active drinkers). Of the two methods, IEF/WB exhibited significantly greater sensitivity than MAEC/RIA for detecting recent, heavy drinking (75% versus 61%, P < 0.05) and generated no false positives whereas MAEC/RIA gave falsely elevated CDT levels in 37% of the abstinent alcoholics.(ABSTRACT TRUNCATED AT 250 WORDS)

Halothane in Children with Chronic Liver Disease

Exacerbation of pre-existing liver disease after halothane anaesthesia has been reported in adult patients. A prospective study was performed in 38 children with biopsy-proven liver disease to assess the effect of surgery and halothane anaesthesia on liver function. Plasma liver enzyme levels were measured immediately preoperatively and again four to eight days after surgery and halothane anaesthesia. Minor elevations of both AST and ALT occurred in four patients but this was not associated with a clinical deterioration in the patients' postoperative recovery. In the children studied pre-existing liver disease did not predispose to a deterioration of liver function following surgery and halothane anaesthesia.

HBV-DNA, HBeAg/anti-HBe serological status in hepatitis B chronic individuals from central Italy

A population of 488 HBsAg carrier individuals, from central Italy, classified on the basis of biochemical, clinical and histological parameters, was analysed for the presence of HBV-DNA in serum and its relationship with HBeAg/anti-HBe markers. The prevalence of HBV-DNA was 32.8% in chronic patients with biopsy-proven liver disease, and 20 and 4.3% respectively in asymptomatic carriers with and without altered ALT levels. The values in chronic patients were correlated with the histological activity. Concordance of HBV-DNA presence and HBeAg positivity was observed in only 61.4% of cases. However HBV-DNA prevalence in sera of anti-HBe positive individuals was very low in asymptomatic carriers with normal ALT levels (2.5%). Higher values were observed in anti-HBe positive chronic patients (15.8%) and in carriers occasionally found with changes in ALT without any other clinical sign of illness (16.7%). These data would indicate that HBV-DNA is the serological marker which is most closely related to liver disease.

Autonomic Neuropathy and Chronic Liver Disease

Autonomic neuropathy has been reported in association with alcoholic cirrhosis but there is no information on its occurrence in non-alcoholic liver disease. We have examined autonomic function in 64 patients with biopsy-proven liver disease (22 with alcoholic liver disease and 42 with non-alcoholic liver disease) together with 29 age-matched controls. Forty-five per cent of patients with alcoholic liver disease and 43 per cent with non-alcoholic liver disease showed evidence of parasympathetic damage; 11 per cent of patients with alcoholic liver disease and 12 per cent with non-alcoholic liver disease had sympathetic damage. Forty-five per cent of patients with alcoholic liver disease and 22 per cent with non-alcoholic liver disease had peripheral neuropathy on clinical examination. Sixty-eight per cent of those with peripheral neuropathy also had autonomic neuropathy. This study confirms that autonomic neuropathy is common in alcoholic patients but the fact that it is found with comparable frequency in non-alcoholic liver disease suggests that the neurological defect may be secondary to the disturbed liver function. The implications of these observations with regard to prognosis of chronic liver disease are discussed.

Modifications of Concanavalin A patterns of α1-acid glycoprotein and α2-HS glycoprotein in alcoholic liver disease

In order to test whether abnormalities in hepatocytes affect the glycoprotein carbohydrate moiety, crossed immunoaffinoelectrophoresis (CIAE) with Concanavalin A (Con A) was used to study serum alpha 1-acid glycoprotein (α1-AGP) and alpha 2-HS glycoprotein (α2-HS) obtained from alcoholic patients with biopsy-proven liver disease. Cirrhotic patients, placed in groups C1, C2 or C3, according to Pugh's classification, were compared to healthy donors (N) and to steatosic non-cirrhotic patients (S). Con A CIAE patterns revealed in group N three subpopulations for α2-HS and four for α1-AGP. Two main results emerged from this study: (1) in the alcoholic groups, the proportions of Con A-unreactive subpopulations of both glycoproteins increased. Moreover, group N could be separated from group S and group S from all the cirrhotic groups. (2) There was a good correlation between the relative amounts in Con A-unreactive subpopulations of α1-AGP and α2-HS. The increases observed in Con A-unreactive subpopulations are probably a general phenomenom related to alterations in glycosylation processing during liver cell damage.

Bentiromide test is not affected in patients with small bowel disease or liver disease.

The bentiromide test reliably detects exocrine pancreatic insufficiency. The synthetic peptide attached to p-aminobenzoic acid (PABA) is cleaved by chymotrypsin, PABA is absorbed in the small intestine, partially conjugated in the liver, and excreted in the urine. It has been claimed that the bentiromide test is abnormal not only in patients with pancreatic insufficiency but also in patients with small bowel or liver disease because of impaired PABA absorption or conjugation, respectively. This study prospectively evaluates the bentiromide test in 12 patients with small bowel disease and 18 patients with biopsy-proven liver disease. One of 30 patients had an abnormal bentiromide test. Cumulative 6-h urinary arylamine excretion and plasma PABA concentration, 2 h after administration, were in the same range as healthy controls. We conclude that the bentiromide test is not affected by small bowel or liver disease. An abnormal test is virtually diagnostic for exocrine pancreatic insufficiency.

FM sonography in diffuse liver disease: prospective assessment and blinded analysis.

FM sonography - a signal-processing technique that uses frequency and phase information as well as amplitude data - shows promise in evaluation of patients with diffuse liver disease. In a prospective blinded review of 37 patients with biopsy-proved liver disease and 42 healthy volunteers, FM sonography was clearly superior to traditional amplitude-based (AM) sonography in distinguishing healthy from diseased subjects. Statistically significant differences were seen in accuracy (FM, 98.7%; AM, 84.8%), sensitivity (FM, 97.3%; AM, 70.3%), and negative predictive value (FM, 97.7%; AM, 78.8%). Our data also suggest that current FM sonographic techniques cannot differentiate among histologic findings associated with different hepatic parenchymal abnormalities. It is unclear, therefore, whether FM imaging can reduce the numbers of patients who require biopsy for diagnosis or the frequency of biopsy procedures in patients with known disease.

ABSENCE OF PRE-S2 ANTIBODIES IN NATURAL HEPATITIS B VIRUS INFECTION

Antibodies to the host "self" component human serum albumin (HSA) and to its receptor are induced by the pre-S2 encoded aminoacid sequence (120-145) of the middle surface protein on the hepatitis B virus (HBV) particle and are produced as part of the immune response during acute HBV-infection. The antibodies disappeared rapidly during the convalescence phase and were not detectable in patients with naturally acquired immunity to HB. These data raise questions about the importance of anti-pre-S2 antibodies for long-term protection against HBV-infection. The coexistence of HBV-DNA with antibodies to native HSA (nHSA) in 13/16 patients with biopsy proven liver disease and of HBV-DNA with anti-pre-S2 in 10/13 patients argues against the attribution of virus eliminating properties to antibodies directed against pre-S2 determinants. In fact circulating anti-nHSA and anti-pre-S2 persisted in 16/17 and 13/17 patients, respectively, with major HBV-induced liver disease but not in symptomless HBsAg carriers. This finding suggests that continuous production of antibodies against the "self" component HSA and/or its receptor structures are associated with the pathogenesis of chronic HBV-induced liver disease. Pre-S2 coded peptide sequences should thus not be incorporated into HB vaccines.

Platelet-associated IgG in hepatitis and cirrhosis.

Increasing evidence is accumulating which indicates that immunological abnormalities contribute to the development of liver disease and its signs and symptoms. Platelet-associated IgG (PAIgG) levels were quantified in 42 patients with biopsy-proven liver disease of various etiologies to determine the relationship of thrombocytopenia to immunologic abnormalities in these disorders. Five of six nonthrombocytopenic patients with acute viral hepatitis B had elevated PAIgG. Six of ten patients with chronic active hepatitis had elevated PAIgG and thrombocytopenia. In contrast, only one of six patients with chronic persistent hepatitis had elevated PAIgG. Nine of ten patients with alcoholic hepatitis had elevated PAIgG; seven of the nine were thrombocytopenic. Seven of ten alcoholic patients with cirrhosis had elevated PAIgG; six of seven were thrombocytopenic. Thus the increase in PAIgG may be present without thrombocytopenia in acute liver injury, while patients with chronic persistent hepatitis do not usually exhibit this abnormality. Severe chronic active liver disease is accompanied by thrombocytopenia and an increase in PAIgG levels.

Dupuytren's contracture, chronic liver disease and IgA immune complexes.

Contrary to previous reports, Dupuytren's contracture was found to be equally common in patients with alcoholic and non-alcoholic biopsy-proven liver disease (25% v 28%). Furthermore, in 69 patients with Dupuytren's contracture referred for surgical correction, there was no significant increase in either history of alcohol abuse or abnormality of liver function compared to a matched control group. Patients with Dupuytren's contracture were found to have increased levels of circulating IgA immune complexes compared to those without (p less than 0.05 for those with liver disease; p less than 0.001 for those awaiting surgical correction). Circulating immunoglobulins and immune complexes of other classes were similar between the groups with and without Dupuytren's contracture. These results suggest that the importance of alcohol has previously been exaggerated but that IgA immune complexes may be involved in the pathogenesis of the condition.

Endogenous bile acid tolerance test for liver function

Fasting and postprandial (stimulated) serum conjugated bile acids (CBA) were measured by a solid-phase radioimmunoassay in 329 patients undergoing liver biopsy, and the results were analyzed for 231 who fitted into 10 diagnostic categories. In healthy volunteers the mean fasting CBA of 1.8 +/- 0.7 mumol/liter rose to 3.0 +/- 0.8 mumol/liter postprandially. In patients mean fasting and stimulated CBA were only significantly raised in moderate to severe chronic and acute liver disease. Diagnostic sensitivity was poor in mild liver disease. Individuals with normal results were found in 8 of 11 disease categories. The ratio of stimulated to fasting CBA expressed in a stimulation quotient did not rise in more advanced liver disease. These findings are best explained by a constant fractional clearance of bile acids by the liver. We conclude that the serum conjugated bile acid determination as a test of liver cell function is not sensitive enough to identify all cases of biopsy-proven liver disease.

Lack of dissociation of prolactin responses to thyrotropin releasing hormone and metoclopramide in chronic alcoholic men.

Prolactin, growth hormone and thyroid stimulating hormone responses to thyrotropin releasing hormone (TRH) and metoclopramide were determined in 12 alcoholic men with biopsy proven liver disease and were compared to those of 8 age matched normal controls. All subjects were challenged with TRH (400 micrograms) and metoclopramide (10 mg) given as an intravenous bolus each on a separate day. Alcoholics had increased basal prolactin and growth hormone levels compared to controls. Alcoholics had a brisk and statistically significant (p less than 0.01) response for each of the 3 hormones studied in response to TRH. In contrast to the alcoholics, the controls did not demonstrate a growth hormone response to TRH. Moreover, the TSH response to TRH of the alcoholics was exaggerated (p less than 0.05) compared to that of the controls. In response to metoclopramide, alcoholics had a brisk prolactin response, failed to demonstrate a TSH response, and had a decline in growth hormone when compared to controls. These results for alcoholics with liver disease differ from those reported for individuals with renal failure while those for the controls are similar to previously reported normal responses. These data suggest that liver disease and renal disease must differ in terms of their patterns of hypothalamic-pituitary neuroregulation as documented by their differing pituitary hormone responses to TRH and metoclopramide.

Effect of Liver Disease Upon Steroid Circadian Rhythms in Man

Summary Steroid circadian variations were studied in 11 patients with biopsy-proven liver disease and compared with observations in eight normal control subjects. Plasma and urinary unconjugated, plasma conjugated, and urinary total 17-hydroxycorticosteroid (17-OHCS) levels were determined in six consecutive 4-hr periods, the plasma levels being measured at the midpoint of each urine collection. In the patients with liver disease, plasma unconjugated as well as conjugated 17-OHCS levels were within the normal range in the morning. Plasma unconjugated 17-OHCS demonstrated a circadian variation within the broad limits of normal in four of eight patients with liver disease studied. In the remaining four, peak levels were maintained longer than normal or else the variation was markedly reduced. Plasma conjugated 17-OHCS showed a slower than normal rise and broader peak resulting in inversion of the normal diurnal rhythm in six of the eight patients investigated. The urinary findings reflected the plasma changes. The 24-hr excretion of free 17-OHCS in the urine was significantly greater than in the normal subjects, whereas total 17-OHCS excretion in contrast was reduced. The observations are in keeping with earlier studies of the effect of liver disease on the disposition of infused cortisol and the response to adrenocorticotropin (ACTH). The findings support the concept of hepatic regulation of pituitary ACTH secretion by the feedback mechanism in that progressive impairment in hepatic degradation of cortisol may lead to a lessened diurnal variation of the unconjugated 17-OHCS, pituitary suppression, and, in turn, reduced adrenocortical cortisol production.