COVID-19 infection in first trimester of pregnancy marked by a liver cytolysis in a woman previously treated by hydroxychloroquine for repeated implantation failure: a case report.

BACKGROUND: In December 2019, a new disease (COVID-19) caused by a novel coronavirus called SARS-CoV-2 emerged in China and spread to many other countries. There is only limited data about the clinical features of COVID-19 during pregnancy, especially in first trimester. CASE PRESENTATION: We report a COVID-19 infection in a 35 years-old patient in first trimester of pregnancy and its consequent medical care. At 7 weeks of pregnancy, the patient, who did not have any pregestational comorbidities, complained of intense nausea and asthenia. An important liver cytolysis was discovered with biological perturbations of transaminases levels. No respiratory symptoms were recorded. Classical viral aetiologies and drug-related toxicity were discarded. Because of the aggravation of the symptoms and the occurrence of the breathlessness, the patient was tested for the COVID-19 in a nasopharyngeal swab. The RTq-PCR assay indicated the presence of SARS-CoV-2 RNA. In the absence of severe symptoms, the patient was monitored at home according to the French government guidelines. After a few days, the symptoms resolved without any complications. The pregnancy is still ongoing without any visible sequelae on the foetus so far. CONCLUSIONS: This first case illustrated the difficulty of COVID-19 diagnosis in patients with isolated digestive symptoms in first trimester of pregnancy that could be confused with gravida hyperemesis. Monitoring of pregnancy after an episode of COVID-19 should be strengthened with bimonthly foetal growth ultrasounds and doppler assessments because of the risks for intrauterine growth restriction. Comprehensive data on larger numbers of first trimester gravid women with COVID-19 are required to better understanding the overall impact of SARS-CoV-2 on maternal and birth outcomes.

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.

Combination of blood tests for significant fibrosis and cirrhosis improves the assessment of liver-prognosis in chronic hepatitis C.

BACKGROUND: Recent longitudinal studies have emphasised the prognostic value of noninvasive tests of liver fibrosis and cross-sectional studies have shown their combination significantly improves diagnostic accuracy. AIM: To compare the prognostic accuracy of six blood fibrosis tests and liver biopsy, and evaluate if test combination improves the liver-prognosis assessment in chronic hepatitis C (CHC). METHODS: A total of 373 patients with compensated CHC, liver biopsy (Metavir F) and blood tests targeting fibrosis (APRI, FIB4, Fibrotest, Hepascore, FibroMeter) or cirrhosis (CirrhoMeter) were included. Significant liver-related events (SLRE) and liver-related deaths were recorded during follow-up (started the day of biopsy). RESULTS: During the median follow-up of 9.5 years (3508 person-years), 47 patients had a SLRE and 23 patients died from liver-related causes. For the prediction of first SLRE, most blood tests allowed higher prognostication than Metavir F [Harrell C-index: 0.811 (95% CI: 0.751-0.868)] with a significant increase for FIB4: 0.879 [0.832-0.919] (P = 0.002), FibroMeter: 0.870 [0.812-0.922] (P = 0.005) and APRI: 0.861 [0.813-0.902] (P = 0.039). Multivariate analysis identified FibroMeter, CirrhoMeter and sustained viral response as independent predictors of first SLRE. CirrhoMeter was the only independent predictor of liver-related death. The combination of FibroMeter and CirrhoMeter classifications into a new FM/CM classification improved the liver-prognosis assessment compared to Metavir F staging or single tests by identifying five subgroups of patients with significantly different prognoses. CONCLUSIONS: Some blood fibrosis tests are more accurate than liver biopsy for determining liver prognosis in CHC. A new combination of two complementary blood tests, one targeted for fibrosis and the other for cirrhosis, optimises assessment of liver-prognosis.

MRI measurement of liver fat content predicts the metabolic syndrome.

BACKGROUND AND AIMS: The prevalence of non-alcoholic fatty liver disease among cardiometabolic patients is not completely known because liver biopsy cannot be routinely performed. However, as magnetic resonance imaging (MRI) allows accurate and safe measurement of the hepatic fat fraction (HFF), the aim of this study was to quantify liver fat content in a dysmetabolic adult population. METHODS: A total of 156 adults were included in this cross-sectional study. Liver and visceral fat were assessed by MRI in these subjects, who presented with zero to five metabolic components of the metabolic syndrome (MetS). Arterial stiffness was recorded by ultrasonography, and the maximum Youden index was used to set the optimal HFF cutoff value predictive of the presence of the MetS. RESULTS: Overall, 72% of participants displayed three or more MetS components. HFF ranged from 0.3% to 52% (mean 13.4%). Age- and gender-adjusted HFF was positively correlated with BMI (r=0.44), blood pressure (r=0.19), triglyceridaemia (r=0.22) and glycaemia (r=0.31). MRI-measured visceral adipose tissue did not influence the relationship of steatosis with glycaemia, HOMA-IR and carotid stiffness, but there was a dose-response relationship between the number of MetS components and mean HFF. The optimal HFF for predicting the MetS was found to be 5.2% according to the maximum Youden index point. CONCLUSION: This study highlighted the impact of liver steatosis on cardiometabolic abnormalities with an optimal cutoff value of 5.2% for defining increased metabolic risk.

Fibrosis progression under maintenance interferon in hepatitis C is better detected by blood test than liver morphometry.

We evaluated whether quantitative measurements of liver fibrosis with recently developed diagnostics outperform histological staging in detecting natural or interferon-induced changes. We compared Metavir staging, morphometry (area and fractal dimension) and six blood tests in 157 patients with chronic hepatitis C from two trials testing maintenance interferon for 96 weeks. Paired liver biopsies and blood tests were available for 101 patients, and there was a significant improvement in Metavir activity and a significant increase in blood tests reflecting fibrosis quantity in patients treated with interferon when compared with controls - all per cent changes in histological fibrosis measures were significantly increased in F1 vs F2-4 stages only in the interferon group. For the whole population studied between weeks 0 and 96, there was significant progression only in the area of fibrosis (AOF) (P = 0.026), FibroMeter (P = 0.020) and CirrhoMeter (P = 0.003). With regards to dynamic reproducibility, agreement was good (r(ic) ≥ 0.72) only for Metavir fibrosis score, FibroMeter and CirrhoMeter. The per cent change in AOF was significantly higher than that of fractal dimension (P = 0.003) or Metavir fibrosis score (P = 0.015). CirrhoMeter was the only blood test with a change significantly higher than that of AOF (P = 0.039). AOF and two blood tests, reflecting fibrosis quantity, have high sensitivity and/or reproducibility permitting the detection of a small progression in liver fibrosis over two years. A blood test reflecting fibrosis quantity is more sensitive and reproducible than morphometry. The study also shows that maintenance interferon does not improve fibrosis, whatever its stage.

A not so solitary fibrous tumor of the liver.

Solitary fibrous tumor (SFT) is a rare neoplasm. Liver parenchyma is a rare location of SFT and, in this case, it usually follows a benign course. We report here the case of a 54-year-old man who presented a large SFT tumor of the right hepatic lobe. The tumor was surgically resected. Local recurrence occurred 6 years later as a 15 cm diameter liver tumor. Histological examination of the resected lesion showed features of an aggressive form of SFT. Two years later, the patient presented with complaints of neck pain and ensuing examinations revealed a tumor of the cranial base. A new surgical resection was performed and histological examination confirmed a metastasis of the SFT. Few weeks later, the patient presented an irreducible psoitis due to an iliac bone metastasis. He died within 1 month.

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.

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.

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).

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.

Improving estimation of liver fibrosis using combination and newer noninvasive biomarker scoring systems in hepatitis C-infected haemophilia patients.

Non-invasive biomarkers have gained popularity for estimating fibrosis stage. In our hepatitis C-infected haemophilia patients, Fibrotest (FT) correctly identified clinically advanced or minimal liver disease. More accurate tests, like the FibroMeters, have recently been validated. The aim of the study was to improve the estimation of liver fibrosis in hepatitis C-infected haemophiliacs using a combination of biomarkers and FibroMeters. One hundred and thirty-two hepatitis C-infected haemophilia patients (124 male, mean age: 39+/-14 years) were evaluated. The following biomarkers were used: FT, AST-to-platelet ratio index (APRI), Forns index, hyaluronic acid and FibroMeter. We applied a published algorithm suggesting that if FT is in concordance with APRI and/or Forns score, then the FT concurs with liver biopsy for estimation of fibrosis. Concordance of three or more biomarkers was present in 43.2% (57/132) of the patients. This high discordance rate was mainly because of indeterminate scores. Significant fibrosis (F2-F4) was estimated at 34.8% (46/132) and 37.9% (50/132) by the FT and FibroMeter respectively. The discordance rate between the FT and FibroMeter was 16.7% (22/132), (P<0.01 vs. other biomarkers). Using the algorithm, liver histology could be confidently estimated in 69.7% (92/132) of the patients. Concordance between the FT and FibroMeter in those patients who met the terms of the algorithm was 90.2% (83/92). Discordance between biomarkers is significant, and is mainly because of biomarkers with indeterminate results. The concordance rate between FT and FibroMeter is higher compared with the other biomarkers. Practical combination of tests may potentially limit the need of liver biopsy in the majority of haemophilia patients.

Fibrinogen angers with a new deletion (gamma GVYYQ 346-350) causes hypofibrinogenemia with hepatic storage.

INTRODUCTION: This study reports a family with chronically abnormal blood liver function tests (LFT) and congenital hypofibrinogenemia. The proposita had cirrhosis initially related to alcohol abuse and chronic viral hepatitis C (HCV), but abnormal LFT persisted even when alcohol intake was stopped and despite HCV treatment was efficient based on serum RNA negative testing. RESULTS: Needle biopsy specimens of the proposita and her brother showed eosinophilic intra-cytoplasmic inclusions that reacted strongly with fibrinogen antisera on direct immunofluorescence. Electron microscopic examination showed that the rough endoplasmic reticulum was filled with inclusions that consisted of densely packed, curved tubular structures arranged in a fingerprint-like pattern. Coagulation studies revealed low functional and antigenic fibrinogen concentrations suggestive of hypofibrinogenemia. Amplification and DNA sequencing showed a heterozygous deletion of the a7690 to g7704 nucleotides of the gamma chain gene in the 3'end of exon 8 (g 7690_7704del14; Genbank access M10014); this deletion encompassed the splicing site at position 7703 and predicts in a new putative consensus splicing sequence (AATGgtatgtt). RNA was extracted from a liver specimen from the proposita's brother. The cDNA obtained by reverse transcription polymerase chain reaction confirmed the usage of a newly generated donor site at position 7688 of the genomic sequence resulting in an in-frame heterozygous 5 amino acid deletion (GVYYQ 346-350; p.G372_Q376del) and that this mutation is responsible for a new splicing site at position 7688 of the genomic sequence. CONCLUSION: we suggest that the molecular defect in fibrinogen Angers results in an impaired assembly and causes defective secretion and hepatic storage of fibrinogen.

In vivo evaluation of lipid nanocapsules as a promising colloidal carrier for paclitaxel.

Paclitaxel-loaded lipid nanocapsules (PX-LNC) exhibit interesting in vitro characteristics with improved antitumoral activity compared with free PX formulation. Biodistribution studies were realized with the use of (14)C-trimyristin ((14)C-TM) or (14)C-phosphatidylcholine ((14)C-PC) whereas antitumoral activity of PX-LNC formulations was based on the animal survival in a chemically induced hepatocellular carcinoma (HCC) model in Wistar rats. Blood concentration-time profiles for both labeled (14)C-TM-LNC and (14)C-PC-LNC were similar; the t(1/2) and MRT values (over 2h and close to 3h, respectively, for both formulations) indicated the long circulating properties of the LNC carrier with a slow distribution and elimination phase. Survival curves of paclitaxel treated groups showed a statistical significant difference compared to the control survival curve (P=0.0036 and 0.0408). Animals treated with 4x 70 mg/m(2) of PX-LNC showed the most significant increase in mean survival times compared to the controls (IST(mean) 72%) and cases of long-term survivors were preferentially observed in the PX-LNC treated group (37.5%; 3/8). These results demonstrate the great interest to use LNC as drug delivery system for paclitaxel, permitting with an equivalent therapeutic efficiency to avoid the use of excipients such as polyoxyethylated castor oil for its formulation.

[Not Available].

Summary A cross-sectional study led in Bamako analyzed the seroprevalence of hepatitis C virus (HCV) and its genotypes among 91 patients carrying chronic liver diseases at the stage of cirrhosis (53) or hepato cellular carcinoma (38) and, on comparative basis in 92 blood donors as control population. False serologic reactions were found with ELISA (3/91 either 3,3% of the liver diseases and 1/92 or 1,1% of the control). Positive tests by ELISA confirmed by a RIBA test were finally considered. Concerning all the liver diseases, the seroprevalence of HCV was 15,4% including 15,1% in cirrhosis, 21% in hepatocellular carcinoma patients versus 2,2% in blood donors. The HBs antigen was associated in 5,6% of the cases In the hepatite C population, genotype 2a/2c was definitely prevalent, about 85,7%. Thus the role of the HCV in genesis of cirrhosis and hepatocellular carcinoma in Mali, appears significant.

[Study of antigen HBs and antivirus antibodies of hepatitis C during hepatopathies in Mali]. / Etude de l'antigène HBs et des anticorps anti-virus de l'hépatite C au cours des hépatopathies chroniques dans des services hospitaliers a Bamako, Mali.

A prospective study carried out in Bamako, Mali between July 1998 and January 1999 has assessed the seroprevalence of hepatitis C virus (HCV) in 91 carrier patients of chronic hepatopathy at a cirrhrosis stage (53) or of hepato-cellular carcinoma (38) and to compare with in 92 blood donors as a control population. Only seroprevalence confirmed by a complementary test has been taken into account (RIBA). HCV seroprevalence reached 25% including all hepatopathies, 24% in cirrhrosis and 26% in hepato-cellular carcinomae (HCC) versus 4% in blood donors. Antigen HBs of hepatitis B virus has been found in 55% of patients, versus 25% of the control cases (p = 0.0006). On the whole, the two markers have been notified a little more often in HCC than in cirrhosis and the combination of the two markers has been more frequent during cirrhosis as well. The role of HCV played in cirrhosis and HCC onset in Mali appears to be important.