ABCB4 gene mutations and single-nucleotide polymorphisms in women with intrahepatic cholestasis of pregnancy.

AIM: To evaluate the nature and frequency of ATP-binding cassette subfamily B member 4 (ABCB4) gene variants in a series of French patients with intrahepatic cholestasis of pregnancy (ICP). METHODS: In this prospective study, the entire ABCB4 gene coding sequence was analysed by DNA sequencing in 50 unrelated women with ICP defined by pruritus and raised serum alanine aminotransferase activity or bile acid concentration, with recovery after delivery. Genomic variants detected in patients with ICP were sought in 107 control pregnant women. Patients with ICP and controls were of Caucasian origin. RESULTS: Eight genomic variants were observed. One nonsense mutation (p.Arg144Stop) and two missense mutations (p.Ser320Phe and p.Thr775Met) were revealed each in one heterozygous patient. A third missense mutation (p.Arg590Gln) was detected in three heterozygous patients and in two homozygous patients also homozygous for a particular haplotype of three single-nucleotide polymorphisms (c.175C>T, c.504T>C, c.711A>T). The chromosomal frequency of the p.Arg590Gln variant was significantly different between the ICP and control group (7.0% vs 0.5%; p = 0.0017; OR 16.03, 95% CI 1.94 to 132.16). An association was also found between allele T of the c.504T>C silent nucleotide polymorphism and ICP (68.0% vs 53.7%; p = 0.017; OR 1.83, 95% CI 1.08 to 3.11). The chromosomal frequency of the p.Arg652Gly variant did not differ between the ICP and control group (p = 0.40). CONCLUSIONS: This study shows that 16% of Caucasian patients with ICP bear ABCB4 gene mutations, and confirms the significant involvement of this gene in the pathogenesis of this complex disorder.

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.

[How to confirm acute fatty liver of pregnancy in case of emergency]. / Comment confirmer le diagnostic de stéatose hépatique aiguë gravidique en urgence?

Acute fatty liver of pregnancy (AFLP) is a rare disease of which prognosis could be adverse if diagnosis is delayed. Certain diagnosis is sometimes made complex because of undercurrent symptoms with pre-eclampsia or hemolysis, elevated liver enzyme, low platelet (HELLP) syndrome. Several reports announce an increase of incidence and illustrate cases confirmed by non-invasive methods. They permit early diagnosis and improve morbidity and mortality. Reviewing seven of the most important series of AFLP, we demonstrate how to use ultrasonography or computed tomography scan to confirm AFLP. However, liver biopsy should be realised after delivery in case of uncertain diagnosis.

[Hepatitis B and pregnancy]. / Hépatite virale B et Grossesse.

In pregnant women, hepatitis B virus (HBV) infection presents the risk of mother-to-child (vertical) transmission. The contaminated newborn most often remains a chronic carrier. Mother-to-child transmission can be avoided by serovaccination of the newborn. Screening for HBs antigen is essential in all pregnant women; in France, it is mandatory at the 6-month prenatal examination. All infants born to mothers who are carriers of HBs antigen must receive a serovaccination against this virus, by intramuscular injection of vaccine and of hepatitis B immune globulin (H-BIG, 100 or 200 IU), in two different sites, in the first hours after birth. Vaccination then continues, according to the recommended protocol. Although the combination of vaccination and H-BIG is very effective in preventing chronic carriage in children (efficacy >90 %), some children may nonetheless be contaminated, especially when the viral load is very high during pregnancy. These women with very high viral loads may receive lamivudine treatment at the end of pregnancy to diminish viral load and thus the risk of chronic carriage in the child; however the role of this drug in this situation is not yet clearly defined. The efficacy of the serovaccination must be confirmed in all children by a serologic examination (HBs antigen and anti-HBs antibodies) at some time after the last vaccination. Children carrying the HBs antigen must be seen by a pediatrician who has experience with viral hepatitis. When HBs antigen is found in a woman during pregnancy, a specialist should be consulted and the family should undergo complete serologic testing (HBs antigen, anti-HBc and anti-HBs antibodies).

[Portal hypertension and pregnancy]. / Grossesse et hypertension portale.

Pregnancy in patients with portal hypertension is rare but worrying for the clinician. Although the effects of portal hypertension during pregnancy have not been fully elucidated, there is an evident increase in morbidity, especially associated with cirrhosis, which justifies the idea of at-risk pregnancy and requires management by a multidisciplinary team. The prevention and treatment of gastrointestinal haemorrhage is quite similar to that in nonpregnant patients. Investigation and management of portal hypertension before and at the beginning of pregnancy can reduce the risks of foetal loss, restricted intra-uterine growth, premature birth and maternal mortality, which are closely related to gastrointestinal haemorrhage. The risks related to the underlying disease, such as liver failure with cirrhosis and thromboembolic risk with vascular diseases associated with thrombophilia must be taken into consideration. Generally, vaginal delivery with early analgesics for the mother assisted by an extraction device should be preferred to caesarean section, which must be reserved for obstetrical indications.

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.

[Intrahepatic cholestasis of pregnancy]. / La cholestase intrahépatique gravidique.

Intrahepatic cholestasis of pregnancy is the most common liver disorder unique to pregnancy in women without hypertension. The cause of intrahepatic cholestasis of pregnancy is still under discussion but genetic and hormonal factors are predominant. The main symptom is skin pruritus, associated with increase in serum transaminase activities and bile acid concentrations. Intrahepatic cholestasis of pregnancy carries a risk for the pregnancy because of preterm delivery and sudden intrauterine fetal death. Ursodeoxycholic acid (usually 1000mg per day or 15mg/kg per day) is currently the most effective pharmacologic treatment. Ursodeoxycholic acid reduces pruritus, transaminases and bile acid levels and probably prematurity without adverse effects. Obstetric management is still under debate. The majority of authors recommend active management with elective delivery usually before or at 38 weeks of gestation according the severity of cholestasis. Prospective controlled studies are required to confirm the benefit of ursodeoxycholic acid treatment on fetal outcome and to clarify the obstetrical management near term.

[Acute fatty liver of pregnancy and mitochondrial fatty acid oxidation. Consequences for the offspring]. / Stéatose hépatique aiguë gravidique et bêta-oxydation mitochondriale des acides gras : conséquences pour l'enfant.

Acute fatty liver of pregnancy (AFLP) is a rare liver disease unique to pregnancy that can lead to acute liver failure. The prognosis, initially often fatal for both mother and child, has been improved by prompt delivery. The diagnosis should be highly suspected if the mother presents epigastric pain, nausea and/or vomiting, or polyuria-polydipsia in the third trimester of pregnancy. AFLP has been found associated with a genetic deficiency of fatty acid beta-oxidation, which may cause sudden death in infancy. Consequently, the mother and her newborn should undergo screening for this deficiency.

[Asymptomatic pneumothorax diagnosis on pre-biopsy sonogram of the liver]. / Découverte d'un pneumothorax lors d'une échographie de repérage avant ponction biopsie hépatique.

Liver biopsy is an invasive procedure which is widely used for the management of liver diseases. An asymptomatic pneumothorax was detected on sonography prior to biopsy for chronic hepatitis C. The complications from biopsy, potentially severe, are decreased by ultrasound guidance. Currently, ultrasound guidance is recommended at the time of liver biopsy.

[Interferon-alpha and ribavirin treatment in a patient with hepatitis C virus-associated cutaneous periarteritis nodosa]. / Périartérite noueuse cutanée associée à une infection par le virus de l'hépatite C, régressive après une bithérapie antivirale.

BACKGROUND: Hepatitis C virus (HCV) frequently causes leucocytoclastic vasculitis as a result of type II or III cryoglobulinemia. HCV-associated vasculitis without cryoglobulinemia is less common. PATIENTS AND METHODS: A 33-year-old woman consulted for infiltrative necrotic purpura of the lower limbs, responsible for leg ulcers measuring less than 1 cm. Histopathological examination revealed vasculitis affecting the hypodermic arterioles and caused by periarteritis nodosa. No extracutaneous involvement was observed. The patient had presented asymptomatic untreated HVC infection (genotype 3) for two years. Antiviral treatment resulted in elimination of the patient's viremia and no relapse of skin lesions was observed two years after the end of treatment. COMMENTS: This patient presented vasculitis due to cutaneous nodular periarteritis associated with HVC without cryoglobulinemia. Hepatic impairment was mild and did not require any antiviral treatment. No further skin involvement was seen after treatment with colchicine and because the patient's viral genotype was favorable, we decided to initiate antiviral therapy. This therapeutic approach should be considered by dermatologists, but it is nevertheless important to assess the risk of interferon-induced aggravation of vasculitis.

[An anicteric cholectasis and nephrotic syndrome: AL amyloïdosis in a 51 years-old man]. / Une cholestase anictérique associée à un syndrome néphrotique chez un homme de 51 ans: découverte d'une amylose AL.

Amyloidosis is a multiple-organ disease for which the diagnosis is often confusing and thereby delayed. Here, we present an archetypal case illustrating such difficulties. A 51 years-old man presented a mixed dyslipemia in November 2002, in June 2004 he has finally been diagnosed with a primary AL-amyloidosis. Within these two years, the arising of a non-icteric cholestasis and a nephrotic syndrome have triggered the search for a disease related to a multiple-organ protein deposition. Confirmation of the AL-amyloidosis was obtained through an histological examination, including direct immuno-fluorescence. Amyloidosis is a life threatening disease that need to be diagnosed at an early stage, in order to maximise the therapeutic expectations. The average survival after the diagnosis of AL-amyloidosis is 5% at 10 years. Often, treatments are initiated late in the course of the disease, at a time when organ lesion are constituted, severely affecting the prognosis.

[Prophylaxis of mother-to-infant transmission of hepatitis B virus]. / Prévention de la transmission materno-infantile du virus de l'hépatite B.

Hepatitis B virus (HBV) infection is a worldwide health problem and mother-to-infant (or vertical) transmission is the main source of chronic infection in Asian countries. Administration of HBV vaccine to the infant at birth, with or without concurrent specific immunoglobulin, efficiently prevents such transmission (efficacy>90%). In France, testing Ag HBs is mandatory during pregnancy in all pregnant women. Infants born to Ag HBs-positive mothers should receive the first injection of vaccine and one injection of specific immunoglobulins at birth. Vaccination should thereafter be completed according to a three-injection protocol (at 1 and 6 months) or a four-injection protocol in case of prematurity. Failure of immunoprophylaxis can be observed when the viral load is very high in the mother during pregnancy (HBV-DNA levels>200,000 IU/mL). In such women, antiviral therapy with analogs (lamivudine, telbivudine, or tenofovir) during the third trimester of pregnancy and 1 month post-partum, in association with accurate immunoprophylaxis, may prevent vertical transmission. The optimal cut-off value of maternal viral load for antiviral therapy in late pregnancy and post-partum to prevent vertical transmission is still under debate.

Protein-energy malnutrition in elderly medical patients.

STUDY OBJECTIVE: To evaluate (1) the prevalence of protein-energy malnutrition in elderly patients; (2) the changes in nutritional status during the hospital stay; and (3) (main objective) the relationship between simple nutritional parameters and short-term in-hospital mortality. DESIGN: Prospective time series at admission and on the 15th day of hospitalization. SETTING: Medical care unit in a teaching hospital. PARTICIPANTS: Consecutive sample of 324 hospitalized patients greater than or equal to 70 years (86.4% of eligible patients). Norms of measurements were obtained from a referred sample of healthy control subjects (26 males and 36 females). MAIN OUTCOME MEASURES: Mid-arm circumference, triceps skinfold thickness, serum albumin, prealbumin, and retinol-binding protein levels were measured in patients at admission and on the 15th day. RESULTS: (1) Prevalence of PEM was 30% in male and 41% in female patients. (2) Both mid-arm circumference and serum albumin level decreased over the first 15 days of hospital stay (53 patients, paired t test, P less than 0.05). Triceps skinfold thickness did not change. (3) A step-wise discriminant-function analysis determined the utility of the parameters at admission as predictors of in-hospital mortality before the 15th day. Mid-arm circumference, triceps skinfold thickness, albumin, and prealbumin levels, as well as age, are predictors of in-hospital mortality, with 73% sensitivity, 69% specificity, and 70% of correctly classified patients of both sexes. CONCLUSIONS: Parameters used are predictors for short-term in-hospital mortality of elderly patients hospitalized in an acute medical unit. The lean body mass is preferentially mobilized for energy during hospitalization.

Specific pruritic diseases of pregnancy. A prospective study of 3192 pregnant women.

BACKGROUND AND DESIGN: For a period of 1 year, all pregnant women presenting with itching were investigated by clinical, histologic, immunopathologic, and laboratory studies. Fifty-one of 3192 pregnant women were studied. RESULTS: We identified (1) two typical cases of herpes gestationis, with an approximate incidence of one in 1700 pregnancies; (2) 22 cases of pruritus gravidarum, including five cases with a polymorphous skin eruption, with an incidence of one in 145 pregnancies; (3) 25 cases of polymorphic eruption of pregnancy, including diseases without maternal or fetal side effects and without criteria defining herpes gestationis or pruritus gravidarum, with an incidence of one in 130 pregnancies; and (4) two cases of intercurrent disease (one scabies and one exfoliative dermatitis). CONCLUSION: Our study is a prospective homogeneous account of pruritic dermatosis of pregnancy. Our results show that the incidence of herpes gestationis is higher than is usually reported in the literature and that pruritus gravidarum must be considered in the presence of itching occurring during pregnancy, with or without skin eruption.

Acute fatty liver of pregnancy.

Acute fatty liver of pregnancy is a rare clinical entity unique to pregnancy that occurs during the third trimester. The obstetric team must be familiar with this disease because early diagnosis and prompt delivery have dramatically improved prognosis, which was often fatal for both mother and child. Clinicians must have a high index of suspicion for this condition when a woman has nausea or vomiting, abdominal pain (particularly epigastric), jaundice, polyuria-polydipsia (without diabetes), increased serum transaminase activity or thrombocytopenia in late pregnancy. The disease rarely recurs during a subsequent pregnancy. The cause is unknown, but some cases of acute fatty liver of pregnancy have been associated with a genetic deficiency of fatty acid beta-oxidation. Because of the possibility of this congenital deficiency, infants of affected mothers should undergo close follow-up from birth.

The American anthropometric norms are not suitable to assess the nutritional status of a French population.

Weight: height2 ratio (W/H2), triceps skinfold thickness (TSF), and mid-upper arm circumference (MAC) were recorded in 254 blood donors aged 20 to 59 yrs (123 men and 131 women), to establish anthropometric data in a healthy sample of the French population. When compared with the American anthropometric norms (HANES I & II), we noted that: (1) the percentiles distribution values of W/H2 were nearly identical; (2) the age and sex-related values of TSF were lower in our study (p < 0.003); (3) our percentiles distribution values of MAC were lower in our study (p < 0.03), except in women 20-39 yrs of age. The variations of TSF and MAC with age and sex were identical in both the French and the American populations: i.e. the MAC values increased with age in both men and women, and the TSF values increased with age only in women. We conclude that the differences noted between the American norms and our anthropometric data plead in favour of the determination of French national anthropometric norms.

Cerebellar hemangioblastoma and primary hyperparathyroidism.

The authors report the case of a 52-year-old woman presenting with cerebellar hemangioblastoma and primary hyperparathyroidism. It is the second reported case involving this new association. The relationship between these two tumors is discussed.

[Carbohydrate-deficient transferrin and liver diseases. Study of 94 patients]. / Transferrine déficiente en acide sialique et maladies du foie. Etude de 94 malades.

OBJECTIVES AND METHODS: Carbohydrate-deficient transferrin has been proposed as a marker of alcohol consumption. The aim of this study was to evaluate the accuracy of the carbohydrate-deficient transferrin serum level, measured by ion exchange chromatography followed by radioimmunoassay (Kit CDTect), for the diagnosis of excessive alcohol intake in patients with liver diseases. Ninety-four patients (68 men, 26 women, age 21-71 years), 42 with alcoholic liver diseases and 52 with non-alcoholic liver diseases, were studied. Twenty-six patients consumed > or = 40 g alcohol per day (mean alcohol intake: 84 +/- 52 g per day) and were considered to be excessive drinkers. RESULTS: The sensitivity of carbohydrate-deficient transferrin for the diagnosis of excessive alcohol intake was 35%, and the specificity was 91%. By pairing carbohydrate-deficient transferrin with other markers of alcohol consumption, the sensitivity of the association of carbohydrate-deficient transferrin and gammaglutamyl transpeptidase was 96%, and the specificity was 59%. CONCLUSION: In patients with liver diseases, carbohydrate-deficient transferrin is a specific marker of excessive alcohol intake but a lack of sensitivity may limit its use.

[Serologic diagnosis and epidemiology of acute delta hepatitis in Indre-et-Loire]. / Diagnostic sérologique et épidémiologique des hépatites aiguës delta en Indre-et-Loire.

A 6 years retrospective study (1981-1986) of 153 consecutive cases of HBsAg positive acute hepatitis was carried out to assess the prevalence of delta virus infections in the Indre-et-Loire a district of the Loire Valley in France. Diagnostic value of the various serum markers of delta infection, i. e. HDAg, anti-HD and anti-HD IgM, were evaluated using immunoenzyme assays. During the survey, 22 cases of delta hepatitis were diagnosed (12 co-infections, 10 superinfections). They all involved young adults, 21 of them were drug-addicts, and one young woman was the consort of a drug-addict. In Indre-et-Loire, delta virus infection was responsible for half of acute HBsAg positive hepatitis among drug-users in the last 3 years of our study. Clinical and biological features of acute delta hepatitis were compared to those of the other HBsAg positive hepatitis: two cases of fulminant hepatitis occurred among the 12 co-infections; 4 of 6 superinfection that could be followed up to 6 months developed biopsy-proven chronic active hepatitis. Delta Ag was found constantly during the first week of the disease, its disappearance was always followed by a seroconversion to anti-HD after four weeks. Anti-delta IgM was an inconstant and late marker: it was detected within the first 4 weeks in only one case (a co-infection); it persisted only in superinfections. Our study shows that delta Ag is an efficient serum marker for the early diagnosis of acute delta hepatitis.

[Decrease of haptoglobin serum level in patients with chronic viral hepatitis C]. / Diminution de l'haptoglobinémie chez les malades atteints d'hépatite chronique virale C.

Serum levels of haptoglobin, an acute phase protein, in usually increased in patients with inflammation and decreased in patients with intravascular hemolysis. Changes in haptoglobin serum levels were also observed in patients with liver disease. The aim of this study was to evaluate the serum level of haptoglobin in patients with chronic viral hepatitis C. Haptoglobin serum levels were measured by rate nephelometry in 34 patients with histologically proven chronic viral hepatitis C and in 30 controls. Haptoglobin serum levels were lower in patients than in controls (0.56 +/- 0.36 versus 0.90 +/- 0.35 g/L, P < 0.001). In patients with chronic hepatitis but without cirrhosis, haptoglobin serum levels were decreased as well. Haptoglobin serum levels were positively correlated to prothrombin index (P < 0.001) and negatively correlated to the histology activity index of Knodell (P < 0.001), and especially to scores of fibrosis (P < 0.001) and periportal necrosis (P < 0.05). Red cell count, indirect bilirubin level, and reticulocyte count, as markers of hemolysis, were similar in patients and controls. We conclude that determination of haptoglobin serum levels may be useful in the evaluation and the follow-up of patients with chronic viral hepatitis C.