Radiation-induced cholangitis with hepatocellular carcinoma.

There are no reports of hepatocellular carcinoma complicating postradiotherapy cholangitis. We report the case of a 45-year-old patient who had undergone upper abdominal radiotherapy for Hodgkin's disease, 21 years before, which was complicated years later by cholangitis with stricture of the common bile duct. Biliodigestive anastomosic surgery was scheduled due to recurrent angiocholitis, and hepatocellular carcinoma was discovered. The patient died from carcinoma some months later.

Liver fibrosis staging with contrast-enhanced ultrasonography: prospective multicenter study compared with METAVIR scoring.

We prospectively assessed contrast-enhanced sonography for evaluating the degree of liver fibrosis as diagnosed via biopsy in 99 patients. The transit time of microbubbles between the portal and hepatic veins was calculated from the difference between the arrival time of the microbubbles in each vein. Liver biopsy was obtained for each patient within 6 months of the contrast-enhanced sonography. Histological fibrosis was categorized into two classes: (1) no or moderate fibrosis (F0, F1, and F2 according to the METAVIR staging) or (2) severe fibrosis (F3 and F4). At a cutoff of 13 s for the transit time, the diagnosis of severe fibrosis was made with a specificity of 78.57%, a sensitivity of 78.95%, a positive predictive value of 78.33%, a negative predictive value of 83.33%, and a performance accuracy of 78.79%. Therefore, contrast-enhanced ultrasound can help with differentiation between moderate and severe fibrosis.

Treatment of liver fibrosis: clinical aspects.

The main objective of antifibrotic treatment is to avoid the complications of chronic liver disease where its cause cannot be treated. Three main therapeutic endpoints can be targeted: cause; comorbidity; and fibrosis. Antifibrotic treatment is any intervention independent of cause that is intended to modify the course and/or level of fibrosis through direct action on the mechanisms of fibrosis. Several modalities are here considered: reduction of fibrosis course; reversion of fibrosis; and reversion of cirrhosis. Semiquantitative histological staging and morphometry are complementary techniques for monitoring fibrosis. The degree of fibrosis should preferentially be estimated by fibrosis progression based on measurements taken at baseline and during treatment, rather than by raw static measurements. Surrogate markers are the only tools for assessing drug efficacy in clinical practice, and are especially useful for checking compliance and identifying poor or non-responders. We propose to define non-response as no decrease in fibrosis progression. The renin-angiotensin system is a good candidate target for antifibrotic treatment, and angiotensin-II type-1 receptor blockers, such as sartans, are probably effective. Clinical trials are currently ongoing using marketed drugs, while new multitargeted drugs are likely to emerge from basic research.

Evaluation and improvement of a reliable diagnosis of cirrhosis by blood tests.

OBJECTIVE: To evaluate the rates of reliable diagnosis of cirrhosis by two usual blood tests. METHODS: Reliable diagnosis was mainly evaluated by comparing rates of positive (PPV) and negative (NPV) predictive values with FibroTest and FibroMeters, as either standard test or specifically designed for cirrhosis, in 1056 patients with chronic hepatitis C. RESULTS: Using the diagnostic limits provided by fibrosis stage scales, the PPV for cirrhosis was: standard FibroMeters: 68.5% versus FibroTest: 37.1%. Using 95% PPV, the cirrhosis detection rate was: specific FibroMeter: 26.1% versus FibroTest: 2.0% (P<10(-3)). The cirrhosis detection rate increased from 26 to 65% by performing liver biopsy in 8% of patients with indeterminate results on specific FibroMeter between 95% NPV and PPV. On the other hand, specific FibroMeter provided three intervals of 95% reliable diagnosis with no biopsy: less than or equal to 95% NPV: no cirrhosis (threshold: diagnosis); significant fibrosis; and greater than or equal to 95% PPV: cirrhosis. CONCLUSION: The detection rate and PPV for cirrhosis using fibrosis scales were fair for standard FibroMeter and poor for FibroTest. Around one-fourth of cases of cirrhosis are detected by the 95% PPV of specific FibroMeter, and around two-thirds by performing an additional liver biopsy in only 8% of patients. Finally, specific FibroMeter can avoid liver biopsy by classifying patients into three categories: no cirrhosis; significant fibrosis; and cirrhosis.

FibroMeters: a family of blood tests for liver fibrosis.

FibroMeters are blood tests for liver fibrosis with several specificities: two main diagnostic targets (fibrosis stage and area of fibrosis); adaptation to specific causes; and results confirmed by an expert system. Thus, FibroMeters comprise six different tests: one for staging and one for quantitation of liver fibrosis in each of the three main causes of chronic liver disease-chronic viral hepatitis, alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). FibroMeters display a high overall diagnostic accuracy and are the only tests to correctly classify 100% of HCV patients without fibrosis or with cirrhosis. They have 90% predictive values in a higher proportion of patients than with other usual blood tests. A 90% correct classification is available in 100% of HCV patients with the following reliable diagnostic intervals: F0/1, F1/2, F2+/-1, F3+/-1. In real-life conditions, the reproducibility of FibroMeters is higher than that of liver biopsy or ultrasonographic elastometry. FibroMeters are robust tests with the most stable diagnostic performance across different centers. Optional tests are also available, such as a specific one for cirrhosis, which has a diagnostic accuracy of 93.0% (AUROC: 0.92) and a 100% positive predictive value for diagnosis of HCV cirrhosis. Determination by FibroMeters of the area of fibrosis - the only direct, non-invasive, quantitative measurement of liver fibrosis - are especially useful for following-up cirrhosis as it correlates well with clinical events. FibroMeters are also very accurate in HVB or HIV-HCV co-infected patients. The tests specific for ALD and NAFLD also have a high diagnostic accuracy (AUROCs: 0.96 and 0.94, respectively, for significant fibrosis).

Suspicious liver nodule in chronic liver disease: Usefulness of a second biopsy.

PURPOSE: To assess the usefulness of a second biopsy when the first one was inconclusive in patients with a liver nodule found during the follow-up for chronic liver disease. MATERIALS AND METHODS: Among 381 patients (544 nodules) included in a prospective study designed to evaluate the accuracy of imaging for the diagnosis of small hepatocellular carcinoma (HCC) in chronic liver disease, 254 nodules were biopsied. The following histological results were considered as conclusive: HCC, dysplastic or regenerative nodule, and other identified tumors (benign or malignant). For nodules with inconclusive results (e.g. fibrosis or no definite focal lesion), a second biopsy was suggested, but was not mandatory. RESULTS: A total of 242 patients (194 men, 48 women; mean age, 61.9±9.5 [SD]; range: 40.2-89.0years) with 254 nodules underwent a first biopsy. Mean nodule diameter was 19.2±5.4mm (range: 10-33mm). The first biopsy was conclusive in 189/254 nodules (74.4%): 157 HCCs (83.1%), 11 regenerative nodules (5.8%), 10 dysplastic nodules (5.3%), 3 cholangiocarcinomas (1.6%), and 8 other tumors (4.2%). Among the 65 nodules for which the first biopsy was inconclusive, a second biopsy was performed for 17 nodules in 16 patients within 6 months of the first one. It was conclusive in 13/17 nodules (76.5%): 10 HCCs (76.9%), 2 dysplastic nodules (15.4%), and 1 other tumor (7.7%). In 4/17 nodules (23.5%), no definitive diagnosis could be provided. CONCLUSION: The diagnostic yield of a second biopsy of a suspicious lesion suggestive of HCC in chronic liver disease is not decreased compared to the first one. Repeated biopsy after a first negative one could be an alternative option to the follow-up of patients with chronic liver disease.

Screening for therapeutic trials and treatment indication in clinical practice: MACK-3, a new blood test for the diagnosis of fibrotic NASH.

BACKGROUND: The composite histological endpoint comprising nonalcoholic steatohepatitis (NASH) and NAFLD activity score ≥4 and advanced fibrosis (F ≥ 2) ("fibrotic NASH") is becoming an important diagnostic target in NAFLD: it is currently used to select patients for inclusion in phase III therapeutic trials and will ultimately be used to indicate treatment in clinical practice once the new drugs are approved. AIM: To develop a new blood test specifically dedicated for this new diagnostic target of interest. METHODS: Eight Hundred and forty-six biopsy-proven NAFLD patients from three centres (Angers, Nice, Antwerp) were randomised into derivation and validation sets. RESULTS: The blood fibrosis tests BARD, NFS and FIB4 had poor accuracy for fibrotic NASH with respective AUROC: 0.566 ± 0.023, 0.654 ± 0.023, 0.732 ± 0.021. In the derivation set, fibrotic NASH was independently predicted by AST, HOMA and CK18; all three were combined in the new blood test MACK-3 (hoMa, Ast, CK18) for which 90% sensitivity and 95% specificity cut-offs were calculated. In the validation set, MACK-3 had a significantly higher AUROC (0.847 ± 0.030, P ≤ 0.002) than blood fibrosis tests. Using liver biopsy in the grey zone between the two cut-offs (36.0% of the patients), MACK-3 provided excellent accuracy for the diagnosis of fibrotic NASH with 93.3% well-classified patients, sensitivity: 90.0%, specificity: 94.2%, positive predictive value: 81.8% and negative predictive value: 97.0%. CONCLUSION: The new blood test MACK-3 accurately diagnoses fibrotic NASH. This new test will facilitate patient screening and inclusion in NAFLD therapeutic trials and will enable the identification of patients who will benefit from the treatments once approved.

Liver fibrosis diagnosis by blood test and elastography in chronic hepatitis C: agreement or combination?

BACKGROUND: In chronic hepatitis C, the European Association for the Study of the Liver and the Asociacion Latinoamericana para el Estudio del Higado recommend performing transient elastography plus a blood test to diagnose significant fibrosis; test concordance confirms the diagnosis. AIM: To validate this rule and improve it by combining a blood test, FibroMeter (virus second generation, Echosens, Paris, France) and transient elastography (constitutive tests) into a single combined test, as suggested by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. METHODS: A total of 1199 patients were included in an exploratory set (HCV, n = 679) or in two validation sets (HCV ± HIV, HBV, n = 520). Accuracy was mainly evaluated by correct diagnosis rate for severe fibrosis (pathological Metavir F ≥ 3, primary outcome) by classical test scores or a fibrosis classification, reflecting Metavir staging, as a function of test concordance. RESULTS: Score accuracy: there were no significant differences between the blood test (75.7%), elastography (79.1%) and the combined test (79.4%) (P = 0.066); the score accuracy of each test was significantly (P < 0.001) decreased in discordant vs. concordant tests. Classification accuracy: combined test accuracy (91.7%) was significantly (P < 0.001) increased vs. the blood test (84.1%) and elastography (88.2%); accuracy of each constitutive test was significantly (P < 0.001) decreased in discordant vs. concordant tests but not with combined test: 89.0 vs. 92.7% (P = 0.118). Multivariate analysis for accuracy showed an interaction between concordance and fibrosis level: in the 1% of patients with full classification discordance and severe fibrosis, non-invasive tests were unreliable. The advantage of combined test classification was confirmed in the validation sets. CONCLUSIONS: The concordance recommendation is validated. A combined test, expressed in classification instead of score, improves this rule and validates the recommendation of a combined test, avoiding 99% of biopsies, and offering precise staging.

Non-invasive assessment of hepatic iron stores by MRI.

BACKGROUND: MRI has been proposed for non-invasive detection and quantification of liver iron content, but has not been validated as a reproducible and sensitive method, especially in patients with mild iron overload. We aimed to assess the accuracy of a simple, rapid, and easy to implement MRI procedure to detect and quantify hepatic iron stores. METHODS: Of 191 patients recruited, 17 were excluded and 174 studied, 139 in a study group and 35 in a validation group. All patients underwent both percutaneous liver biopsy with biochemical assessment of hepatic iron concentration (B-HIC) and MRI of the liver with various gradient-recalled-echo (GRE) sequences obtained with a 1.5 T magnet. Correlation between liver to muscle (L/M) signal intensity ratio and liver iron concentration was calculated. An algorithm to calculate magnetic resonance hepatic iron concentration (MR-HIC) was developed with data from the study group and then applied to the validation group. FINDINGS: A highly T2-weighted GRE sequence was most sensitive, with 89% sensitivity and 80% specificity in the validation group, with an L/M ratio below 0.88. This threshold allowed us to detect all clinically relevant liver iron overload greater than 60 micromol/g (normal value <36 micromol/g). With other sequences, an L/M ratio less than 1 was highly specific (>87%) for raised hepatic iron concentration. With respect to B-HIC range analysed (3-375 micromol/g), mean difference and 95% CI between B-HIC and MR-HIC were quite similar for study and validation groups (0.8 micromol/g [-6.3 to 7.9] and -2.1 micromol/g [-12.9 to 8.9], respectively). INTERPRETATION: MRI is a rapid, non-invasive, and cost effective technique that could limit use of liver biopsy to assess liver iron content. Our MR-HIC algorithm is designed to be used on various magnetic resonance machines.

Radiological treatment of HCC: Interventional radiology at the heart of management.

Interventional radiology is involved practically at each stage in the treatment of hepatocellular carcinoma, as recommended in the EASL-EORTC guidelines. It is even becoming more important as technological advances progress and as its long-term efficacy is assessed. Used curatively, thermoablation can obtain five-year survival rates of 40 to 70%, with a survival rate of 30% at 10years. As there are many tools available in order to be used, it requires a thorough pre-treatment assessment and discussion in a multidisciplinary team meeting. Regular patient reassessment is needed in order to be able to adjust treatment because of the complementarity of the treatments available and the course of the disease.

New method of cardiac output measurement using ultrasound velocity dilution in rats.

The aim of this study was to validate a new technique for the measurement of cardiac output (CO) based on ultrasound and dilution (COUD) in anesthetized rats. A transit time ultrasound (TTU) probe was placed around the rat carotid artery, and ultrasound velocity dilution curves were generated on intravenous injections of saline. CO by COUD were calculated from the dilution curves for normal and portal hypertensive rats in which CO was known to be increased. COUD was compared with the radiolabeled microsphere method and with direct aortic TTU flowmetry for baseline CO and drug-induced CO variations. CO in direct aortic TTU flowmetry was the ascending aorta blood flow measured directly by TTU probe (normal use of TTU flowmetry). The reproducibility of COUD within the same animal was also determined under baseline conditions. COUD detected the known CO increase in portal hypertensive rats compared with normal rats. CO values by COUD were correlated with those provided by microsphere technique or direct aortic TTU flowmetry (adjusted r = 0.76, P < 10(-4) and r = 0.79, P < 0.05, respectively). Baseline CO values and terlipressin-induced CO variations were detected by COUD and the other techniques. Intra- and interobserver agreements for COUD were excellent (intraclass r = 0.99 and 0.98, respectively). COUD was reproducible at least 10 times in 20 min. COUD is an accurate and reproducible method providing low-cost, repetitive CO measurements without open-chest surgery. It can be used in rats as an alternative to the microsphere method and to direct aortic flowmetry.

Late recurrence of a hepatic angiomyolipoma.

Angiomyolipomas are benign mesenchymal tumours, mostly of renal origin. Hepatic angiomyolipomas are rare, and radiological and pathological diagnoses may be difficult We report on the first case of hepatic angiomyolipoma recurrence known to us, 6 years after surgical treatment of the initial tumour. Moreover, this hepatic recurrence was associated with renal angiomyolipoma without any stigmata of tuberous sclerosis.

Hepatic hyper-vitaminosis A: importance of retinyl ester level determination.

We report the case of a 32-year-old man with portal hypertension without cirrhosis due to chronic vitamin A intoxication. Portal hypertension revealed by oesophageal varice rupture progressively worsened and ascites occurred 5 years after the patient stopped vitamin A intake. Initially, serum retinyl palmitate concentration was increased whereas serum retinol concentration was normal. There was no hepatic fibrosis on light microscopic examination of liver biopsy specimens. Five years after the patient stopped excessive vitamin A intake, serum retinol and retinol-binding protein concentrations were below the normal range even though there was an increased hepatic retinyl ester content. This was attributed to the late development of peri-sinusoidal fibrosis. This case mainly shows the importance of retinyl ester level determination: serum retinyl palmitate should be measured immediately after intoxication and hepatic retinyl esters should be measured initially and particularly later. Indeed, later serum and hepatic retinol levels in chronic hyper-vitaminosis A may be normal and lead to under-estimation of liver vitamin A overload.

Lack of effect of propranolol in the prevention of large oesophageal varices in patients with cirrhosis: a randomized trial. French-Speaking Club for the Study of Portal Hypertension.

OBJECTIVE: Beta-blockers have been shown to reduce portal pressure in patients with cirrhosis and limit the development of portosystemic shunts in portal hypertensive animals. Thus, a randomized double-blind trial was conducted to evaluate propranolol in the prevention of the development of large oesophageal varices in patients with cirrhosis without varices or with small varices. METHODS: One hundred and two patients received long-acting propranolol (160 mg/day) and 104 patients received a placebo. At inclusion, there was no significant difference between the two groups in terms of clinical characteristics or biochemical tests. At 2 years, the size of varices was estimated on video recordings. RESULTS: One-third of the patients were lost to follow-up, and 95%/97% of the remaining patients were compliant in the propranolol and placebo groups, respectively. At 2 years, the proportion of patients with large varices was 31% in the propranolol group and 14% in the placebo group (P< 0.05). Three and four patients bled in the propranolol and placebo groups, respectively, and nine and ten died, respectively. CONCLUSION: This trial suggests that propranolol administration cannot be recommended for the prevention of the development of large oesophageal varices in patients with cirrhosis; thus other studies are needed in selected subgroups of patients.

[Hematologic manifestations related to hepatitis A virus. 3 cases]. / Manifestations hématologiques liées au virus de l'hépatite A. Trois cas.

We report 3 cases of acute hepatitis A infection with haematological manifestations. In the first case, severe aplastic anemia occurred in a 6 year-old child, who underwent 3 bone marrow grafts before responding favourably. In the second and third cases, severe anemia and thrombocytopenia occurred in a 42 year-old man with cholestatic hepatitis, and in a 66 year-old man with fulminant hepatitis; there was a favourable outcome in both cases. These cases demonstrate that haematological manifestations in hepatitis A can be severe, independent of the severity of liver disease. Although these manifestations seem to be rare, we suggest performing systematic haematological evaluations in cases of viral hepatitis A with unusual outcomes.

[Association of hepatic adenomatosis and hepatoportal sclerosis in a woman with incontinentia pigmenti]. / Association d'une adénomatose hépatique et d'une sclérose hépatoportale chez une femme atteinte d'incontinentia pigmenti.

We report the case of the association of three uncommon diseases in a young woman: incontinentia pigmenti, portal hypertension due to hepatoportal sclerosis, and liver adenomatosis. Incontinentia pigmenti is a hereditary genodermatosis with pigmentary cutaneous lesions and dysmorphic malformations. In our patient, among liver abnormalities, there were blood biochemical alterations, portal hypertension, and initially neo hepatic nodular lesions. Histological examination of the surgical liver specimen showed several adenomas and fibrosis of the portal tracts with portal vascular changes. The etiopathogenic nature of the adenomatosis and hepatoportal sclerosis is unclear. As a general rule, hepatic adenomatosis is associated with normal liver. We hypothesize that the adenomas could be secondary to changes in hepatic vascularisation.

[Follow-up of blood donors with positive serology for hepatitis C virus and their recipients is insufficient]. / Le suivi des donneurs de sang ayant une sérologie du virus de i'hépatite C positive et de leurs receveurs est insuffisant.

OBJECTIVES: Our aim was to study the characteristics of blood donors with serum anti-HCV antibodies, their medical follow-up based on a questionnaire, and the follow-up of their recipients who were transfused before systematic screening of anti-HCV antibodies had begun. METHODS: From March 1990 to January 1992, 25,255 blood donors were tested by ELISA 1 or ELISA 2 serum tests and confirmed by RIBA 2 test in case of positivity: 126 (0.5%) were ELISA positive of whom 40 (0.16%) were RIBA 2 positive (n = 18) or indeterminate (n = 22); among the latter, 13 were retested by RIBA 3 which was positive in 2 cases. Thus, the prevalence of blood donors with truly positive HCV antibodies testing was shown to be between 0.08 and 0.12%. Among the 126 ELISA positive blood donors, 90 had given blood before systematic screening had begun, involving 232 patients and 50 non nominative products. RESULTS: In donors with positive ELISA test, the prevalence of serum ALT activity > 2N was 17% if the RIBA test was positive vs 1% if the test was negative or indeterminate (P = 0.0007). The rate of donors with serum ALT activity > N before March 1990 was 62.5% if the RIBA test was positive vs 17.5% if it was negative (P = 0.01). The follow-up at 2 years of 34 out of 40 donors with a positive or indeterminate RIBA test showed that 88% had had at least two serum ALT activity tests, that 12% had had a serologic test, that 6% had sought the advice of a specialist, and that a liver biopsy was performed in 3%. The follow-up of recipients showed that the response rate of physicians or recipients was 37% (47% at public hospital and 12% in private hospital, P < 0.01). The rate of recipients positive for HCV was 25%, that is 2% of the entire group, yielding an estimated 8% efficiency of the survey. Lack of screening was due to the lack of responses from physicians or recipients in 64% of cases and to the death of the recipient in 36% of cases. CONCLUSION: HCV seroprevalence among blood donors in France is closed to that observed in Northern Europe. In this population, there is a great discrepancy between the ELISA and RIBA tests. During the survey period, the follow-up of HCV positive blood donors seemed to be very insufficient. The screening of their recipients was poorly effective, thus emphasizing the importance of the systematic and prospective follow-up of blood donors.

[Suicidal impulses in patients with chronic viral hepatitis C during or after therapy with interferon alpha]. / Pulsions suicidaires chez des malades atteints d'hépatite chronique C au cours ou au décours du traitement par l'interféron alpha.

UNLABELLED: We report 5 cases of psychiatric side effects in patients treated with alpha interferon for chronic viral C hepatitis. The first case includes depression with suicidal impulses without a suicide attempt; there was a positive rechallenge of interferon. In the second and third cases, depression occurred during interferon therapy, but has not disappeared after interferon withdrawal. In the 4th and 5th cases, depression occurred after interferon withdrawal. Overall, suicide was attempted in 4 cases after interferon withdrawal and was responsible for 2 deaths. The prevalence of suicide attempts during the 6 to 12 months of interferon therapy was 0% compared to 1.3% during the 6 months after interferon therapy (P < 0.05) in 306 patients with chronic hepatitis C treated by interferon in our local area network during the same period. IN CONCLUSION: a) depression does not always disappear after interferon is discontinued; b) regular psychiatric follow-up is justified during treatment with interferon; c) psychiatric supervision should be continued, even more frequently after interferon withdrawal; d) the increased risk of psychiatric side-effect due to interferon as well as their severity suggest interferon should be administered with caution; e) the role of interferon can only be evaluated in controlled studies including the incidence and predictive value of emotional disorders.

[Budd-Chiari syndrome due to membranous obstruction of the inferior vena cava of congenital origin. Ten-year follow-up after radiologic treatment]. / Syndrome de Budd-Chiari par obstruction membraneuse de la veine cave inférieure d'origine congénitale. Suive de 10 ans après traitment radiologique.

We report a case of Budd-Chiari syndrome due to membranous obstruction of the inferior vena cava with a congenital malformation composed of a left inferior vena cava at the sub-renal level with an azygo-caval continuation without a retrohepatic segment of the inferior vena cava. To our knowledge, this is the first report of this association. The congenital venous malformation suggests a congenital etiology to the inferior vena cava membrane. The membranous obstruction was treated by percutaneous transluminal angioplasty. During the 10-year follow-up, there was no recurrence of the membranous obstruction as seen with Doppler ultrasound and magnetic resonance imaging.