Hepatocellular carcinoma in patients with metabolic dysfunction-associated fatty liver disease: Can we stratify at-risk populations?

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new nomenclature recently proposed by a panel of international experts so that the entity is defined based on positive criteria and linked to pathogenesis, replacing the traditional non-alcoholic fatty liver disease (NAFLD), a definition based on exclusion criteria. NAFLD/MAFLD is currently the most common form of chronic liver disease worldwide and is a growing risk factor for development of hepatocellular carcinoma (HCC). It is estimated than 25% of the global population have NAFLD and is projected to increase in the next years. Major Scientific Societies agree that surveillance for HCC should be indicated in patients with NAFLD/ MAFLD and cirrhosis but differ in non-cirrhotic patients (including those with advanced fibrosis). Several studies have shown that the annual incidence rate of HCC in NAFLD-cirrhosis is greater than 1%, thus surveillance for HCC is cost-effective. Risk factors that increase HCC incidence in these patients are male gender, older age, presence of diabetes and any degree of alcohol consumption. In non-cirrhotic patients, the incidence of HCC is much lower and variable, being a great challenge to stratify the risk of HCC in this group. Furthermore, large epidemiological studies based on the general population have shown that diabetes and obesity significantly increase risk of HCC. Some genetic variants may also play a role modifying the HCC occurrence among patients with NAFLD. The purpose of this review is to discuss the epidemiology, clinical and genetic risk factors that may influence the risk of HCC in NAFLD/MAFLD patients and propose screening strategy to translate into better patient care.

Nonalcoholic fatty liver disease associated with metabolic syndrome: Influence of liver fibrosis stages on characteristics of very low-density lipoproteins.

BACKGROUND: We evaluated possible changes in VLDLcharacteristics, and metabolic related factors, in MetS-associated NAFLD and accompanying liver fibrosis. METHODS: We studied 36 MetS patients with biopsy-proven NAFLD (MetS+NAFLD) and 24 MetS without ultrasound NAFLD evidence. Further, MetS+NAFLD was sub-divided according to fibrosis stage into, non-to-moderate (F0-F2, n=27) and severe (F3-F4, n=9) fibrosis. We measured: lipid profile, VLDL composition and size (size exclusion-HPLC), CETP and lipoprotein lipase (LPL) activities and adiponectin. Additionally, in MetS+NAFLD type IV collagen 7S domain was measured. RESULTS: MetS+NAFLD showed increased VLDL-mass, VLDL particle number, VLDL-triglyceride% and large VLDL-% (p<0.04). CETP activity tended to increase in MetS+NAFLD (p=0.058), while LPL activity was unchanged. Moreover, in MetS+NAFLD, adiponectin was decreased (p<0.001), and negatively correlated with VLDL-mass and VLDL particle number (p<0.05), independently of insulin-resistance. Within MetS+NAFLD group, despite greater insulin-resistance, patients with severe fibrosis showed lower plasma triglycerides, VLDL-mass, VLDL-triglyceride%, large VLDL-% and CETP activity (p<0.05), while type IV collagen was increased (p=0.009) and inversely correlated with large VLDL-% (p=0.045). CONCLUSIONS: In MetS, NAFLD is associated with larger and triglyceride over-enriched circulating VLDLs, of greater atherogenicity. However, when NAFLD progresses to severe fibrosis, circulating VLDL features apparently improved, probably due to early alterations in hepatic synthetic function.

Effect of cirrhosis at baseline on the outcome of type 1 autoimmune hepatitis.

MATERIAL AND METHODS: With the aim of analyzing the influence of presence of cirrhosis at baseline on the outcome, we revised the evolution of a cohort of patients with type 1 autoimmune hepatitis, prospectively followed at a single hospital. 139 patients (113 females, 26 males), median age 45.7 years, interquartile range 13-59 years, were followed-up for a median period of 58 months (interquartile range 27-106). RESULTS: At baseline, 55 patients had cirrhosis and they were significantly older, had lower prothrombin activity and serum albumin than patients without cirrhosis. In contrast, patients without cirrhosis had significantly higher bilirubin, AST and ALT levels at diagnosis time. There was no significant difference in the follow-up time between patients with and without cirrhosis at baseline and either in the percentage of patients receiving immunosupresor treatment (80 vs. 91%, respectively) or in the response to therapy (complete response in 82 vs. 95%, respectively). However, patients with cirrhosis had a significantly lower probability of remaining free of cirrhosis complications (49.1% at 102 months, 95%CI, 35.5-67.9% vs. 86.7%, 95%CI, 77.1%-97.5%, respectively) (p = 0.0000) and a significantly lower overall survival at 120 months (67.1%, 95%CI, 51.3-87.6 vs. 94.4%, 95%CI, 86.9-100%, respectively) (p = 0.003) than those without cirrhosis at presentation. CONCLUSION: Patients with type 1 autoimmune hepatitis and cirrhosis at presentation have a lower survival than those without cirrhosis despite a similar response to treatment.

Comparison of NAFLD fibrosis score and BARD score in predicting fibrosis in nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Liver biopsy (LB) is the only means to evaluate fibrosis in NAFLD. Two scoring systems, NAFLD fibrosis score and BARD score, were proposed to separate cases with and without severe fibrosis (SF). Our aim was to compare the utility of both scores in patients with biopsy-proven NAFLD. METHODS: 138 consecutive patients of our series were included (67 male, median age 49 years). A NAFLD fibrosis score lower than -1.455 would exclude SF. A score greater than 0.676 would predict SF. An intermediate score is defined as indeterminate. The BARD score ranges from 0 to 4. Scores 0-1 are considered to have a high negative predictive value (NPV) for SF. The results of the scores were compared with LB staging. NPV, positive predictive value (PPV) and area under the ROC curve (AUROC) were calculated for both systems. RESULTS: A total of 37 patients had SF. NAFLD fibrosis score was indeterminate in 42 cases. Among the 91 patients with low score, 74 did not have SF but 17 patients had SF. All of 5 patients with a high score had SF. Sensitivity was 22.7%; specificity, 100%; NPV, 81.3%; and PPV, 100%. The BARD score was low in 96 patients and high in 42. Among the 96 patients with a low score, 78 did not have SF but 18 did. Among 42 patients with a high score, 19 had SF. Sensitivity was 51.4%; specificity, 77.2%; NPV, 81.3%; and PPV, 45.2%. AUROC were 0.68 (95% CI, 0.57-0.78) and 0.67 (95% CI, 0.56-0.77) for NAFLD fibrosis and BARD scores, respectively. CONCLUSIONS: Both systems were useful in identifying patients without SF (NPV 81.3%) but the BARD score is easier to estimate and does not have indeterminate results.

Etiology of hepatocellular carcinoma in Argentina: results of a multicenter retrospective study.

Incidence and etiology of hepatocellular carcinoma (HCC) are variable around the world, depending mainly on theprevalence ofchronic hepatitis B carriers in each region. No study has been published analyzing epidemiological features of patients with HCC in Argentina. The aim of this retrospective study was to describe demographical and etiological results in a series of 587 consecutive patients with HCC diagnosed in 15 Hepatology and Gastroenterology Units distributed all around our country. Seventy-two per cent of patients were male, the median age was 62 years (interquartile range 55-68 years), and 93% had cirrhosis. Regarding to etiological data (fully available in 551 cases), main etiologies were chronic alcoholism in 229 patients (41.6%) (the sole risk factor in 182, associated to HCVin 35 and to HBV in 12); hepatitis C in 223 patients (40.5%) (the sole risk factor in 181, associated to alcoholism in 35 and to HBV in 7); hepatitis B in 74 patients (13.4%) (the sole risk factor in 55, associated to alcoholism in 12 and to HCV in 7); cryptogenic cirrhosis in 51 patients (9.2%). There were significant differences in percentages of genders between main groups: males were highly predominant in alcoholic cirrhosis (93%), hepatitis B (87%) and HCV plus alcohol (94%), compared to 63% in cryp togenic cirrhosis and 49% in hepatitis C (p<0.01). There were no differences in age at presentation between the main etiologies. In conclusion, the main causes of HCC in Argentina are alcoholic cirrhosis and hepatitis C (76% of cases). A majority of patients with HCC in our country are cirrhotics, males, and in their 6th or -7th decades of life.

Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies.

Nonalcoholic steatohepatitis may cause severe fibrosis, cirrhosis, and hepatocellular carcinoma, but supporting evidence is based on indirect data. Few publications have examined the results of repeat liver biopsies to evaluate progression of fibrosis. The aims of this study were to assess rate of fibrosis progression in untreated patients with nonalcoholic steatohepatitis and to identify associated variables. Among 106 patients, a second liver biopsy was proposed to those who had undergone their first liver biopsy at least 3 years before. None of them had been given pharmacological therapy. Liver biopsy samples were evaluated blindly. Variables were compared between patients with (group P) and without (group NP) fibrosis progression, using a Wilcoxon rank-sum test for numerical variables and a difference of two binomial proportions for categorical ones. Twenty-two patients (median age, 45 years; age range, 20-69 years; 13 women; diabetes in 8 patients, obesity in 10 patients) underwent a second liver biopsy 4.3 years (range, 3.0-14.3 years) after the first. Fibrosis progression was found in 7 patients in group P (31.8%), no progression was found in 15 patients in group NP. There were no differences between both groups regarding age, gender, diabetes, hyperlipidemia, ALT levels, AST-to-ALT ratio levels, albumin levels, prothrombin activity, steatosis, or inflammation. Obesity was significantly more prevalent in group P (86%) than in group NP (27%; P =.01). Basal body mass index was higher in group P (median, 33.2; range, 29.1-38.2) than in group NP (median, 29.0; range, 24.0-38.1; P =.024). Time between biopsies was not different between groups. In conclusion, progression of liver fibrosis was found in a third of nonalcoholic steatohepatitis patients 4.3 years after the first liver biopsy, and obesity and body mass index were the only associated factors with such progression.

Nadolol plus spironolactone in the prophylaxis of first variceal bleed in nonascitic cirrhotic patients: A preliminary study.

Treatment with beta-blockers fails to decrease portal pressure in nearly 40% of cirrhotic patients. Recent studies have suggested that treatment with spironolactone reduces pressure and flow in the portal and variceal systems. This trial was designed to assess if nadolol plus spironolactone is more effective than nadolol alone to prevent the first variceal bleeding. One hundred patients with medium and large varices who had never bled and were without ascites were included in a prospective, randomized, multicenter, double-blind, placebo-controlled trial. The patients were randomized into 2 groups: 51 received nadolol plus placebo (N + P) and 49 received nadolol plus spironolactone 100 mg/d (N + S). Hepatic venous pressure gradient (HVPG) and activity of the renin-aldosterone system (plasma renin activity/plasma aldosterone levels) were measured in 24 patients. There were no significant differences in the appearance of variceal bleeding and ascites between groups at a mean follow-up of 22 +/- 16 months. However, analyzing both complications together, the incidence was significantly higher in the N + P group than in the N + S group (39% vs. 20%; P <.04). Clinical ascites was also higher in patients in the N + P group than in the N + S group (21% vs. 6%; P <.04). Significant increases in plasma renin activity and plasma aldosterone levels were only observed in patients in the N + S group (P <.01). The cumulative probabilities of remaining free of bleeding and ascites were similar in both groups after 70 months of follow-up. In conclusion, these results suggest that nadolol plus spironolactone does not increase the efficacy of nadolol alone in the prophylaxis of the first variceal bleeding. However, when bleeding and ascites were considered together, the combined therapy effectively reduced the incidence of both portal-hypertensive complications.

Ascites due to hypothyroidism in a patient with alcoholic cirrhosis

Myxedema is the cause of ascites in less than 1 per cent of new-onset ascites cases, where as only 4 per cent of patients with hypothyroidism present ascites. When ascites is the first manifestation of thyroid insufficiency, there is usually a delay in diagnosis. We report here a case of myxedema ascites occuring in a patient with alcoholic cirrhosis, that was first thought to be the cause of the ascites, and review the features of 48 cases previously reported. Some clinic and analytical findings that have been commonly reported, are the prompt response (with resolution of ascites) to thyroid replacement treatment, a high total protein concentration in ascitec fluid, white moderate white blood cell counts and a lymphocyte predominance. Serum-ascites albumin gradient has been postulated to be high in myxedema ascites, but we believe this has been studied in too few cases thus far, to be conclusive. (Au)

Ascites due to hypothyroidism in a patient with alcoholic cirrhosis

Myxedema is the cause of ascites in less than 1 per cent of new-onset ascites cases, where as only 4 per cent of patients with hypothyroidism present ascites. When ascites is the first manifestation of thyroid insufficiency, there is usually a delay in diagnosis. We report here a case of myxedema ascites occuring in a patient with alcoholic cirrhosis, that was first thought to be the cause of the ascites, and review the features of 48 cases previously reported. Some clinic and analytical findings that have been commonly reported, are the prompt response (with resolution of ascites) to thyroid replacement treatment, a high total protein concentration in ascitec fluid, white moderate white blood cell counts and a lymphocyte predominance. Serum-ascites albumin gradient has been postulated to be high in myxedema ascites, but we believe this has been studied in too few cases thus far, to be conclusive.

Interferon alfa en el tratamiento de la hepatitis cronica C: curso de 24 versus 48 semanas. Resultados de un estudio randomizado / Interferon alfa in the treatment of chronic hepatitis C: course of 24 versus 48 weeks. Results of a randomized trial

The aim of this trial was to investigate if a more prolonged course of interferon (IFN) is able to increase the long-term benefit in patients with chronic hepatitis C. Forty-four patients with active chronic hepatitis and antibodies to HCV were randomly assigned to receive IFN-alfa 2b 3 MU t.i.w. during 24 weeks (group I, n 23) or during 48 weeks (group II, n 21). In the evaluation of results, complete response was considered when the ALT values returned to normality during the treatment; and sustained response, when the ALT values persisted below normal range during at least 6 months post therapy. Histologic changes were compared by using the Histological Activity Index, or Knodell score. Viremia status was evaluated for the study of HCV RNA (by nested-RT-PCR). Results: There were no significant differences between boths groups before treatment, in terms of age, sex, ALT, or histologic findings (11 patients in group I, and 7 in group II had cirrhosis). Complete response was found in 9 patients (39.1 per cent) from group I; in 11 (52.4 per cent) from group II (NS). Basal histologic findings were identified as the only predictive factor of complete and sustained response, by logistic regresion analysis. Considering only noncirrhotic patients, complete response was seen in 58.3 per cent in patients from group I, 71.4 per cent in group II. Sustained response was obtained in 4 patients from group I, (17.4 per cent), 7 from group II (33.3 per cent) (NS). Post IFN liver biopsies were performed in 23 patients (12 from group I, 11 from group II). In group I patients, there were no significant changes. In group II, Knodell score was found to be significantly decreased post IFN (pre IFN, median 10, range 3-15; post IFN, median 6, range 2-14) (p<0.05). HCR RNA was absent in serum during the follow-up post IFN in 2 patients from group I, in 3 from group II. The results of this study show that a 48 weeks course of IFN has a trend to achieve a higher sustained response than the usual regime (but non significant); and it produces a decrease in the histologic activity. The best predicitve factor of positive response was the absence of cirrhosis in our study (although we did not evaluate viral factors, such as genotypes or HCV viremia levels). (AU)

Interferon alfa en el tratamiento de la hepatitis cronica C: curso de 24 versus 48 semanas. Resultados de un estudio randomizado / Interferon alfa in the treatment of chronic hepatitis C: course of 24 versus 48 weeks. Results of a randomized trial

The aim of this trial was to investigate if a more prolonged course of interferon (IFN) is able to increase the long-term benefit in patients with chronic hepatitis C. Forty-four patients with active chronic hepatitis and antibodies to HCV were randomly assigned to receive IFN-alfa 2b 3 MU t.i.w. during 24 weeks (group I, n 23) or during 48 weeks (group II, n 21). In the evaluation of results, complete response was considered when the ALT values returned to normality during the treatment; and sustained response, when the ALT values persisted below normal range during at least 6 months post therapy. Histologic changes were compared by using the Histological Activity Index, or Knodell score. Viremia status was evaluated for the study of HCV RNA (by nested-RT-PCR). Results: There were no significant differences between boths groups before treatment, in terms of age, sex, ALT, or histologic findings (11 patients in group I, and 7 in group II had cirrhosis). Complete response was found in 9 patients (39.1 per cent) from group I; in 11 (52.4 per cent) from group II (NS). Basal histologic findings were identified as the only predictive factor of complete and sustained response, by logistic regresion analysis. Considering only noncirrhotic patients, complete response was seen in 58.3 per cent in patients from group I, 71.4 per cent in group II. Sustained response was obtained in 4 patients from group I, (17.4 per cent), 7 from group II (33.3 per cent) (NS). Post IFN liver biopsies were performed in 23 patients (12 from group I, 11 from group II). In group I patients, there were no significant changes. In group II, Knodell score was found to be significantly decreased post IFN (pre IFN, median 10, range 3-15; post IFN, median 6, range 2-14) (p<0.05). HCR RNA was absent in serum during the follow-up post IFN in 2 patients from group I, in 3 from group II. The results of this study show that a 48 weeks course of IFN has a trend to achieve a higher sustained response than the usual regime (but non significant); and it produces a decrease in the histologic activity. The best predicitve factor of positive response was the absence of cirrhosis in our study (although we did not evaluate viral factors, such as genotypes or HCV viremia levels).