Daniel S. Matloff

Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis

BACKGROUND/AIMS A total of 213 patients with compensated cirrhosis, portal hypertension and no varices were included in a trial evaluating beta-blockers in preventing varices. Predictors of the development of hepatocellular carcinoma (HCC), including hepatic venous pressure gradient (HVPG) were analyzed. METHODS Baseline laboratory tests, ultrasound and HVPG measurements were performed. Patients were followed prospectively every three months until development of varices or variceal bleeding or end of the study in 09/02. The endpoint was HCC development according to standard diagnostic criteria. Univariate and multivariate Cox regression models were developed to identify predictors of HCC. RESULTS In a median follow-up of 58 months 26/213 (12.2%) patients developed HCC. Eight patients were transplanted and 28 patients died without HCC. Twenty-one (84%) HCC developed in patients with HCV. On multivariate analysis HVPG (HR 1.18; 95%CI 1.08-1.29), albumin (HR 0.34; 95%CI 0.14-0.83) and viral etiology (HR 4.59; 95%CI 1.51-13.92) were independent predictors of HCC development. ROC curves identified 10 mmHg of HVPG as the best cut-off; those who had an HVPG above this value had a 6-fold increase in the HCC incidence. CONCLUSIONS Portal hypertension is an independent predictor of HCC development. An HVPG >10 mmHg is associated with a 6-fold increase of HCC risk.

Osteoporosis in Primary Biliary Cirrhosis: Effects of 25-Hydroxyvitamin D3 Treatment

Bone histology, bone mineral content, and calcium absorption were evaluated in 10 patients with primary biliary cirrhosis and osteopenia, before and after 1 yr of treatment with oral 25-hydroxycholecalciferol. Before treatment, quantitative histomorphometric analysis of full-thickness iliac crest bone biopsy specimens with double-tetracycline labeling demonstrated that 9 of 10 patients had osteoporosis. None had osteomalacia. Fasting intestinal calcium absorption correlated well with trabecular bone volume (r = 0.85). Bone mineral content measured by 125I-photon absorption was low in 6 of 10 patients, and it correlated poorly with iliac crest trabecular bone volume. After 1 yr of treatment with oral 25-hydroxyvitamin D3, bone mineral content fell in all 8 patients who were restudied. Iliac crest trabecular bone volume increased in 3 patients, 2 of whom had the greatest pretreatment impairment in calcium absorption, but fell in 5. Bone fractures continued to occur in 3 of 5 patients who were alive after 1 yr and developed for the first time in a sixth patient. We conclude that 25-hydroxyvitamin D3 is ineffective in reversing the bone thinning in the majority of primary biliary cirrhosis patients, but it may be helpful in a few selected patients.

A Prospective Trial of D-Penicillamine in Primary Biliary Cirrhosis

We evaluated D-penicillamine in the treatment of primary biliary cirrhosis. In a prospective double-blind trial, 26 patients received D-penicillamine (250 mg four times a day), and 26 received an identical placebo. Although the desired urinary excretion of copper was achieved in patients taking D-penicillamine, there was no improvement in survival or symptoms after 28 months. Serum bilirubin and alkaline phosphatase increased equally in both groups. Alanine and aspartate aminotransferases were lower in the D-penicillamine group, but serum albumin was also lower in this group. Liver histology worsened equally in both groups. Major side effects, some appearing more than 24 months after the start of treatment, occurred in 31 per cent of the patients receiving D-penicillamine. Less serious side effects occurred in an additional 46 per cent. We conclude that D-penicillamine at the dosage we used is not effective in the treatment of primary biliary cirrhosis and is associated with a high incidence of serious side effects.

Incidence, Prevalence, and Clinical Significance of Abnormal Hematologic Indices in Compensated Cirrhosis

BACKGROUND & AIMS Patients with cirrhosis develop abnormal hematologic indices (HI) from multiple factors, including hypersplenism. We aimed to analyze the sequence of events and determine whether abnormal HI has prognostic significance. METHODS We analyzed a database of 213 subjects with compensated cirrhosis without esophageal varices. Subjects were followed for approximately 9 years until the development of varices or variceal bleeding or completion of the study; 84 subjects developed varices. Abnormal HI was defined as anemia at baseline (hemoglobin, < or =13.5 g/dL for men and 11.5 g/dL for women), leukopenia (white blood cell counts, < or =4000/mm3), or thrombocytopenia (platelet counts, < or =150,000/mm3). The primary end points were death or transplant surgery. RESULTS Most subjects had thrombocytopenia at baseline. Kaplan-Meier analysis showed that leukopenia occurred by 30 months (95% confidence interval, 18.5-53.6), and anemia occurred by 39.6 months (95% confidence interval, 24.1-49.9). Baseline thrombocytopenia (P = .0191) and leukopenia (P = .0383) were predictors of death or transplant, after adjusting for baseline hepatic venous pressure gradient (HVPG), and Child-Pugh scores. After a median of 5 years, a significant difference in death or transplant, mortality, and clinical decompensation was observed in patients who had leukopenia combined with thrombocytopenia at baseline compared with patients with normal HI (P < .0001). HVPG correlated with hemoglobin and white blood cell count (hemoglobin, r = -0.35, P < .0001; white blood cell count, r = -0.31, P < .0001). CONCLUSIONS Thrombocytopenia is the most common and first abnormal HI to occur in patients with cirrhosis, followed by leukopenia and anemia. A combination of leukopenia and thrombocytopenia at baseline predicted increased morbidity and mortality.

Obesity is an independent risk factor for clinical decompensation in patients with cirrhosis

Obesity is associated with an aggressive course in chronic viral hepatitis; however, its impact in the development of clinical decompensation (CD) in patients with established cirrhosis is uncertain. We evaluated the role of obesity, in relationship to other recognized predictors, in the development of CD in patients with compensated cirrhosis. The study population, a subset of patients included in a randomized trial of beta‐blockers in the prevention of varices in whom data on body mass index (BMI) was available, consisted of 161 patients with compensated cirrhosis. Laboratory tests and portal pressure (assessed by the hepatic venous pressure gradient or HVPG) were assessed on inclusion. Patients were followed until CD (ascites, hepatic encephalopathy, or variceal hemorrhage), or until September 2002. Altogether, 29% had a normal BMI, 40% were overweight, and 30% were obese. In a median follow‐up of 59 months, CD occurred in 48/161 (30%) patients with an increasingly higher rate according to BMI group (15% in those with normal BMI; 31% in overweight; 43% in obese patients, P = 0.011). The actuarial probability of developing CD was significantly higher in the abnormal BMI groups (P = 0.022). In a multivariate model that included parameters previously identified as being predictive of CD (HVPG, albumin, Mayo endstage liver disease score), etiology, and treatment group, BMI (hazard ration 1.06; 95% confidence interval 1.01‐1.12), P = 0.02] was an independent predictor of decompensation, together with HVPG and albumin. Conclusion: Obesity has a deleterious effect on the natural history of compensated cirrhosis of all etiologies, independent of portal pressure and liver function. Weight reduction may be a valuable therapeutic measure in this patient population. (HEPATOLOGY 2011;)

Platelet count is not a predictor of the presence or development of gastroesophageal varices in cirrhosis.

Current guidelines recommend esophagogastroduodenoscopy (EGD) in patients with cirrhosis to screen for gastroesophageal varices (GEV). Thrombocytopenia has been proposed as a noninvasive test to predict the presence of GEV. There is no agreement regarding a specific platelet count (PLT) that can reliably predict GEV. The present longitudinal study aims to (1) further investigate the relationship between varices and PLT at the time of endoscopy, (2) investigate whether changes in PLT from the baseline over time can predict the development of GEV, and (3) investigate whether changes in PLT correlate with the hepatic venous pressure gradient (HVPG). A secondary analysis was conducted for 213 subjects with compensated cirrhosis with portal hypertension but without GEV enrolled in a randomized, placebo‐controlled, double‐blind trial of a nonselective beta‐blocker used to prevent GEV. PLTs were obtained every 3 months, and HVPG measurements and EGD were done annually. The PLTs were compared between subjects who did and did not develop GEV. In a median follow‐up of 54.9 months, 84 patients developed GEV. PLT was greater than 150,000 in 15% of patients at the development of GEV. A receiver operating curve did not show any PLT with high sensitivity or specificity for the presence of GEV. Subjects with clinically insignificant portal hypertension (HVPG < 10 mm Hg) whose PLT remained greater than 100,000 had a 2‐fold reduction in the occurrence of GEV (P = 0.0374). A significant correlation was found between HVPG and PLT at the baseline, year 1, and year 5 (P < 0.0001). Conclusion: Cross‐sectional or longitudinal evaluations of PLTs are inadequate noninvasive markers for GEV. Patients with mild portal hypertension whose PLT remains greater than 100,000 have significantly less risk of GEV. Although HVPG correlates somewhat with PLT, changes in PLT cannot be used as a surrogate for HVPG changes. (HEPATOLOGY 2008;47:153–159.)

Evidence against an immune complex pathogenesis of primary biliary cirrhosis.

In an attempt to confirm the presence of immune complexes in the sera of patients with primary biliary cirrhosis, sera of patients with primary biliary cirrhosis were studied with four sensitive radioimmunoassays. Thirty-one sera from 27 patients with well-characterized primary biliary cirrhosis, stages 1–4, were negative for immune complexes using three assays, the monoclonal rheumatoid factor inhibition assay, the C1q binding inhibition assay, and the C1q solid-phase assay. Nine of 31 sera were weakly positive with the C1q binding assay. Attempts at confirming the presence of immune complexes in sera positive in the C1q binding assay were unsuccessful because none of the sera were sufficiently positive for the reactant to be studied after fractionation. The positivity in the C1q binding assay was not due to greater sensitivity of that assay. Two assays used, the monoclonal rheumatoid factor binding inhibition assay and the C1q solid-phase assay, were 2–3 times more sensitive than the C1q binding assay. Neither could the negative results be explained by processing or storage artifacts because immediate assays of freshly drawn sera were also negative. There were no inhibitors of immune complex assays in our primary biliary cirrhosis sera. The addition of primary biliary cirrhosis sera that were negative for immune complexes to lupus serum did not inhibit the detection of immune complexes in lupus serum. To eliminate the likelihood that our negative results were due to some unrecognized methodologic problem in our own laboratory, we sent 25 primary biliary cirrhosis sera to an independent laboratory that used the Raji cell assay. Twenty-two of 25 sera were negative. In addition, at least one-third of the serum reactivity in the three positive sera was due to substances other than immune complexes. The data strongly suggest that circulating immune complexes are not involved in the pathogenesis of primary biliary cirrhosis.

γ-Glutamyl transpeptidase activity in liver disease: serum elevation is independent of hepatic GGTP activity

gamma-Glutamyl transpeptidase activity was measured in liver and serum from 110 patients undergoing diagnostic liver biopsy, including patients with alcoholic liver disease, fatty liver not due to alcohol, primary biliary cirrhosis, persistent hepatic disease, chronic active hepatitis and normal livers. Serum gamma-glutamyl transpeptidase was markedly elevated in patients with alcoholic liver disease and primary biliary cirrhosis while mean hepatic gamma-glutamyl transpeptidase activity was significantly increased only in the alcoholic liver disease group. There was considerable overlap of individual enzyme values among the different disease groups. There was no inhibitors or activators of liver gamma-glutamyl transpeptidase in any of these disorders. The increased liver activity was not related to the degree of hepatic fibrosis or cirrhosis. There was no correlation between hepatic and serum gamma-glutamyl transpeptidase activity. Hepatic and serum gamma activities were equally increased in individuals with alcoholic liver disease whether or not they were drinking at the time of the study. The data suggest that increased hepatic gamma-glutamyl transpeptidase activity is neither specific for alcoholic liver disease nor essential for serum GGTP to be elevated.

Novel inflammatory biomarkers of portal pressure in compensated cirrhosis patients

The rationale for screening inflammatory serum biomarkers of the hepatic vein pressure gradient (HVPG) is based on the fact that portal hypertension is pathogenically related to liver injury and fibrosis, and that in turn these are associated with the activation of inflammatory pathways. This was a nested cohort study in the setting of a randomized, clinical trial to assess the development of gastroesophageal varices (GEV) (N Engl J Med 2005;353:2254). Patients had cirrhosis and portal hypertension but did not have GEV. A total of 90 patients who had baseline day‐1 sera available were enrolled in the present study. The objective of this study was to determine whether inflammatory biomarkers in conjunction with clinical parameters could be used to develop a predictive paradigm for HVPG. The correlations between HVPG and interleukin (IL)‐1β (P = 0.0052); IL‐1R‐α (P = 0.0085); Fas‐R (P = 0.0354), and serum VCAM‐1 (P = 0.0007) were highly significant. By using multivariate logistic regression analysis and selected parameters (transforming growth factor beta [TGFβ]; heat shock protein [HSP]‐70; at‐risk alcohol use; and Child class B) we could exclude HVPG ≥12 mmHg with 86% accuracy (95% confidence interval [CI]: 67.78 to 96.16%) and the sensitivity was 87.01% (95% CI: 69.68 to 96.34%). Therefore, the composite test could identify 86% of compensated cirrhosis patients with HVPG below 12 mmHg and prevent unnecessary esophagogastroduodenoscopy with its associated morbidity and costs in these patients. Our diagnostic test was not efficient in predicting HVPG ≥12 mmHg. Conclusion: A blood test for HVPG could be performed in cirrhosis patients to prevent unnecessary esophagogastroduodenoscopy. (Hepatology 2014;59:1052–1059)

S1918 A Hemodynamic Response to Treatment With Non-Selective Beta-Blockers Protects Against Worsening of Thrombocytopenia in Cirrhosis

patients followed in an academic liver clinic. RESULTS. The study assessed 1,022 patients with a mean 20.0 (3-60) months of follow-up. The mean age was 45.6 (17-86) years; 29.8% (n=304) were elderly (age ≥ 60 years); 54.0% were males; 35.4% were Asians and 41.3%, Caucasians; 44.9% had chronic hepatitis C (CHC) and 19.0%, chronic hepatitis B (CHB). CHC was more common (77.8% vs. 67.4%), but CHB was less common (22.2% vs. 32.6%) in the elderly group than in the younger group, and the frequency of alcoholic liver diseases (ALD) was comparable in both groups (3.3 vs. 3.3%). Elderly patients had significantly higher incidence of history of hypertension (HTN, 50.0% vs. 23.5%), diabetes mellitus (DM, 28.5% vs. 13.6%), but lower incidence of obesity (22.4% vs. 29.0%). They also carried a significantly higher rate of cirrhosis (i.e., stage 3-4 fibrosis) and/or HD (i.e., presence of ascites and/or hepatic encephalopathy, 62.8% vs. 48.5%), and hepatocellular carcinoma (HCC, 8.3% vs. 1.9%). Laboratorially, elderly patients had significantly higher incidence of thrombocytopenia (28.8% vs. 16.4%), hypoalbuminemia (28.2% vs. 17.0%), and AST/ALT ratio ≥ 1 (57.2% vs. 38.3%). Multivariate analyses indicated that the significantly higher frequency of cirrhosis and/or HD in the elderly group was independently associated with age (p=0.003, OR=1.86) and obesity (p=0.0001, OR=2.11). CONCLUSIONS. In this large cohort of patients, elderly patients carried a higher frequency of CHC, history of DM, HTN, cirrhosis and/or HD, and HCC. Cirrhosis was independently associated with age and obesity.