Daniel Dhumeaux

Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C

Liver fibrosis is the main predictor of the progression of chronic hepatitis C, and its assessment by liver biopsy (LB) can help determine therapy. However, biopsy is an invasive procedure with several limitations. A new, noninvasive medical device based on transient elastography has been designed to measure liver stiffness. The aim of this study was to investigate the use of liver stiffness measurement (LSM) in the evaluation of liver fibrosis in patients with chronic hepatitis C. We prospectively enrolled 327 patients with chronic hepatitis C in a multicenter study. Patients underwent LB and LSM. METAVIR liver fibrosis stages were assessed on biopsy specimens by 2 pathologists. LSM was performed by transient elastography. Efficiency of LSM and optimal cutoff values for fibrosis stage assessment were determined by a receiver‐operating characteristics (ROC) curve analysis and cross‐validated by the jack‐knife method. LSM was well correlated with fibrosis stage (Kendall correlation coefficient: 0.55; P < .0001). The areas under ROC curves were 0.79 (95% CI, 0.73‐0.84) for F ≥ 2, 0.91 (0.87‐0.96) for F ≥ 3, and 0.97 (0.93‐1) for F = 4; for larger biopsies, these values were, respectively, 0.81, 0.95, and 0.99. Optimal stiffness cutoff values of 8.7 and 14.5 kPa showed F ≥ 2 and F = 4, respectively. In conclusion, noninvasive assessment of liver stiffness with transient elastography appears as a reliable tool to detect significant fibrosis or cirrhosis in patients with chronic hepatitis C. (HEPATOLOGY 2005;41:48–54.)

Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver diseases

A proper diagnosis of cirrhosis is essential for the management of patients with chronic liver diseases. We assessed the accuracy of liver stiffness measurement by Fibroscan for the diagnosis of cirrhosis in 1,257 patients with chronic liver diseases of various causes enrolled in a prospective multicenter study as well as clarified causes of discrepancies between liver histology and Fibroscan. One hundred thirty‐two patients had unsuitable biopsy specimens, and 118 had unreliable liver stiffness measurements. Because 232 patients overlapped with a previous study, analysis was performed in the 775 new patients then derived in the whole population (1,007; 165 cirrhosis). Diagnostic accuracy was assessed by receiver operator curve (ROC) analysis. Liver samples were re‐analyzed in case of discrepancies. The area under the ROC (AUROC) was 0.95 (95% CI, 0.93‐0.96) for the diagnosis of cirrhosis in either 775 or 1,007 patients. The cutoff value with optimal diagnosis accuracy was 14.6 kPa in 1,007 patients (positive and negative predictive values, 74% and 96%) with discrepancies among the etiological groups. Eighty patients were misclassified: (1) among 45 patients without cirrhosis with liver stiffness 14.6 kPa or greater, 27 (60%) had extensive fibrosis and 10 (22%) significant perisinusoidal fibrosis; and (2) among 35 patients with cirrhosis and liver stiffness less than 14.6 kPa, 10 (29%) had a macronodular pattern and 25 (71%) either none or mild activity. In conclusion, Fibroscan is a reliable method for the diagnosis of cirrhosis in patients with chronic liver diseases, better at excluding than at predicting cirrhosis using a threshold of 14.6 kPa. False‐negatives are mainly attributable to inactive or macronodular cirrhosis. (HEPATOLOGY 2006;44:1511–1517.)

Assessment of biliary fibrosis by transient elastography in patients with PBC and PSC.

Noninvasive measurement of liver stiffness with transient elastography has been recently validated for the evaluation of hepatic fibrosis in chronic hepatitis C. The current study assessed the diagnostic performance of liver stiffness measurement (LSM) for the determination of fibrosis stage in chronic cholestatic diseases. One hundred one patients with primary biliary cirrhosis (PBC, n = 73) or primary sclerosing cholangitis (PSC, n = 28) were prospectively enrolled in a multicenter study. All patients underwent liver biopsy (LB) and LSM. Histological and fibrosis stages were assessed on LB by two pathologists. LSM was performed by transient elastography. Efficiency of LSM for the determination of histological and fibrosis stages were determined by a receiver operating characteristics (ROC) curve analysis. Analysis failed in six patients (5.9%) because of unsuitable LB (n = 4) or LSM (n = 2). Stiffness values ranged from 2.8 to 69.1 kPa (median, 7.8 kPa). LSM was correlated to both fibrosis (Spearmans ρ = 0.84, P < .0001) and histological (0.79, P < .0001) stages. These correlations were still found when PBC and PSC patients were analyzed separately. Areas under ROC curves were 0.92 for fibrosis stage (F) ≥2, 0.95 for F ≥ 3 and 0.96 for F = 4. Optimal stiffness cutoff values of 7.3, 9.8, and 17.3 kPa showed F ≥ 2, F ≥ 3 and F = 4, respectively. LSM and serum hyaluronic acid level were independent parameters associated with extensive fibrosis on LB. In conclusion, transient elastography is a simple and reliable noninvasive means for assessing biliary fibrosis. It should be a promising tool to assess antifibrotic therapies in PBC or PSC. (HEPATOLOGY 2006;43:1118–1124.)

Characteristics of patients with dual infection by hepatitis B and C viruses

BACKGROUND/AIMS The purpose of this study was to compare the epidemiological, biochemical, virological and histological characteristics of patients with chronic hepatitis B and C with those of patients suffering from chronic hepatitis C alone. METHODS Twenty-three patients with chronic hepatitis C, who were anti-HCV positive and HBs antigen positive, were studied and subdivided into two groups according to the presence or absence of HBV DNA replication. They were compared to 69 age- and sex-matched patients with chronic hepatitis who were anti-HCV positive and HBs antigen negative. All patients were HCV RNA positive by PCR, anti-HIV negative and anti-HDV negative. HBV DNA and HCV RNA were detected in serum by means of a branched DNA assay and PCR. The HCV serotypes were determined by the Chiron Riba HCV serotyping SIA technique. The histological characteristics included the Knodell score. RESULTS Epidemiological, biochemical and virological parameters were not different between the two groups. Only the prevalence of cirrhosis was greater in chronic hepatitis B and C patients than in patients with chronic hepatitis C alone (p = 0.01). Among chronic hepatitis B and C patients, HCV RNA level was significantly lower in HBV DNA positive than in HBV DNA negative patients (p = 0.01). Indeed, histological lesions were more severe in HBV DNA positive than in HBV DNA negative patients, including prevalence of cirrhosis (p = 0.01), Knodell score (p = 0.05) and, among the latter, piecemeal necrosis (p = 0.01) and fibrosis (p = 0.05). The characteristics of patients with dual infection did not differ according to the mode of contamination and duration of HBV disease, except for a shorter duration in patients contaminated by drug abuse than in other patients. CONCLUSIONS These results suggest that HBV DNA replication inhibits HCV RNA replication in patients with chronic active hepatitis B and C but increases the severity of histological lesions.

Extrahepatic Immunologic Manifestations in Chronic Hepatitis C and Hepatitis C Virus Serotypes

Extrahepatic immunologic abnormalities have been shown to occur frequently in patients with chronic hepatitis C virus (HCV) infection. Hepatitis C virus now appears to cause those cases of mixed cryoglobulinemia that were previously considered essential [1-5]. Indeed, HCV RNA has been detected in the serum specimens of about 90% of patients with essential mixed cryoglobulinemia [1, 2, 4]. In addition, cryoglobulin is found, usually at low levels, in the serum specimens of one third to one half of patients with chronic hepatitis C [6, 7]; rheumatoid factor, which may play a role in cryoglobulinemia, is present in the serum specimens of about 70% of patients [6]. Various autoantibodies have been seen in the serum of 40% to 50% of patients with chronic HCV infection [6, 8], and HCV has been associated with cases of autoimmune thyroiditis [9]. Salivary gland lesions, characterized by lymphocytic capillaritis, are seen in about half of patients and are sometimes associated with lymphocytic sialadenitis resembling that of the Sjogren syndrome [6]. Finally, HCV may cause the chronic liver disease frequently associated with lichen planus [10]. Recently, sequences of different HCV variants were classified into different genotypes on the basis of overall sequence similarity [11-22]. A consensus nomenclature for HCV genotypes has been proposed [23], in which the six HCV genotypes identified so far are numbered in the order of their discovery. Within each genotype, subtypes have been identified by lower case letters, which are also given in order of discovery [23]. Correspondence among the classifications reported so far is presented in Table 1. Different techniques for determining HCV genotype have been developed in recent months. Currently, in addition to sequencing the genome, investigators can use three techniques based on the polymerase chain reaction (PCR). The technique described by Okamoto and colleagues [24, 25] is based on a nested PCR amplification of the HCV genome and uses primers located in the core region: The first round of PCR uses a pair of universal (non-type-specific) primers and the second uses a pair of type-specific primers. The method of McOmish and colleagues [17, 18] is based on PCR amplification of the 5 noncoding region of the genome done with a pair of universal primers, followed by enzymatic digestion of the amplified products and analysis of their restriction fragment length polymorphism. Stuyver and colleagues described a line probe assay for the determination of HCV genotypes [22], in which a PCR amplification is done using universal primers located in the 5 noncoding region of the genome. This is followed by hybridization of the amplified products to oligonucleotide probes attached as parallel bands on nitrocellulose strips. On the other hand, a serotyping immunoenzymatic assay to detect genotype-specific antibodies directed to epitopes encoded by the NS4 region of the HCV genome has been developed [26]. This technique, in its present form, allows the differentiation of HCV serotypes 1, 2, and 3, which correspond to HCV genotypes 1, 2, and 3 in the consensus nomenclature [23]. Table 1. Correspondence between the Major Published Classification Systems for Hepatitis C Virus Genotypes* Several studies indicate that particular HCV genotypes are associated with more severe liver disease and poorer response to interferon- therapy [27-30]. The factors determining immunologic abnormalities in patients with chronic hepatitis C are largely unknown. We used a serotyping assay to study whether the occurrence of extrahepatic immunologic abnormalities in patients with chronic hepatitis C is serotype dependent. Methods Patients Fifty-nine consecutive patients with chronic hepatitis C were prospectively studied. Thirty-four were men and 25 were women; their mean age was 52 years (range, 18 to 77 years). In all cases, the diagnosis of chronic hepatitis C was based on long-term elevation of serum alanine aminotransferase levels in the blood, positive serologic markers of HCV infection (found using second-generation enzyme-linked immunosorbent assay and recombinant immunoblot assay, Ortho Diagnostic Systems, Raritan, New Jersey), and the absence of any other cause of chronic liver disease. Specimens obtained by percutaneous liver biopsy showed chronic active hepatitis in all 56 patients tested and associated cirrhosis in 15 of the 56 (27%). Before any treatment was given, serum specimens were tested for cryoglobulin, rheumatoid factor, and many antitissue antibodies, and biopsy of labial salivary glands was done. Hepatitis C virus serotype was determined in all patients by immunoenzymatic assay. Study Methods Detection of Cryoglobulinemia Venous blood (20 mL) was taken from fasting patients in a room at 37 C, allowed to clot at this temperature, and then separated by centrifugation. After centrifugation, the supernatant was removed from the serum, incubated at 4 C for 8 days, and examined daily for cryoprecipitation. Detection of Rheumatoid Factor Rheumatoid factor was measured using a nephelometer analyzer (BNA, Behring, Marburg, Germany); polystyrene particles coated with human globulin were agglutinated when mixed with samples containing rheumatoid factor. Normal values were those less than 18 IU/mL. Detection of Autoantibodies Antinuclear, anti-smooth muscle, type 1 anti-liver-kidney microsomal (anti-LKM1), and antimitochondrial antibodies were detected by indirect immunofluorescence using air-dried cryostat sections from rat or mouse livers and kidneys and HEp-2 cells (Kallestad, Chaska, Minnesota) as substrates. Antithyroid microsomal antibodies were detected by indirect immunofluorescence using surgical specimens of human thyrotoxic thyroid as substrate. In all cases, the classic Weller and Coon indirect immunofluorescence method was used with fluorescein-labeled goat immunoglobulin directed to IgG, IgA, and IgM (Pasteur Diagnostics, Marnes la Coquette, France) as a second layer [31]. The serum specimens were tested undiluted for anti-DNA antibodies, at a 1/5 dilution for antimicrosomal antibodies, and at a 1/10 dilution for other antibodies. The titers were established using increasing dilutions up to 1/2560. Antithyroglobulin antibodies were detected using an hemagglutination kit (Thymune-T, Wellcome Diagnostics, Dartford, United Kingdom). Labial Salivary Gland Examination All biopsies were done in macroscopically normal mucosa. The samples were fixed in Bouin fluid, embedded in paraffin, and stained with hematoxylin-eosin-safranin. All sections were examined blind by two pathologists and graded according to the Chisholm and Mason classification system [32]. Determination of Serotypes The 59 serum specimens in our study were tested for the presence of serotype-specific antibodies using the recently developed enzyme immunoassay [26]. A series of eight branched peptides, synthesized from two antigenic regions of HCV genotypes 1, 2, and 3, were used to coat polypropylene microtiter wells overnight at 4 C. After washing, the wells were blocked with 150 L of blocking solution (phosphate-buffered saline, 0.1% Tween 20, and 2% bovine serum albumin) for 1 hour at room temperature. Blocking assays were done using mixes of type-specific peptides at a final concentration of 1 mg/mL (for example, 100:1 excess over that used to coat the wells). Plasma specimens from the 59 patients were diluted in the blocking solution and 100 L were added to antigen-coated and blocked wells. The first incubation was done overnight at 4 C. Plates were washed four times in phosphate-buffered saline and 0.1% Tween 20 and then incubated with horseradish peroxidase-conjugated anti-human IgG (1/20 000 in phosphate-buffered saline and 0.1% Tween 20 for 1 hour at room temperature). The plates were finally washed four times in phosphate-buffered saline and 0.1% Tween 20 and incubated with substrate (50 g of O-phenylenediamine per milliliter and 0.1% H2O2 [30 volumes] for 30 minutes in the dark at room temperature). Optical densities were read at 490 nm; values ranged from 100 to 2000 mU. Results Prevalence of Immunologic Abnormalities Our results are presented in Table 2. Cryoglobulin was found in the serum specimens of 20 of the 56 patients tested (36%), and rheumatoid factor was present at abnormal levels in 42 of the 59 patients (71%). Table 2. Prevalence of the Different Immunologic Abnormalities according to Hepatitis C Virus Serotype At least one type of antitissue antibody was detected in the serum specimens of 24 of the 59 patients (41%). Thirteen patients (22%) had serum antinuclear antibodies and 13 (22%) had anti-smooth muscle antibodies at a significant titer (greater than 1/40). Anti-LKM1 antibodies were found in 3 patients (5%) and antithyroid antibodies were found in 5 (8%); 4 of these 5 had antithyroglobulin and 1 had antithyroid microsomes. No antimitochondrial antibodies were found. Labial salivary gland biopsies were done in those 49 of the 59 patients who had no contraindication and who gave informed consent; lesions were found in 24 of them (49%). In all patients, these lesions were characterized by lymphocytic capillaritis, as previously described [6]. In 7 patients (14%), they were associated with more severe lesions, grades 3 and 4 by the Chisholm and Mason classification (lymphocytic sialadenitis) [32], and resembled the lymphocytic sialadenitis of the Sjogren syndrome (14%). Only one of the patients with salivary gland lesions had a mild case of the ocular sicca syndrome shown by the Schirmer test. The prevalences of the different immunologic abnormalities did not vary significantly according to the presence of cirrhotic findings in liver specimens. Hepatitis C Virus Serotypes Thirty-five of the 59 patients (59%) were infected with HCV serotype 1, 6 (10%) were infected with serotype 2, and 7 (12%) were infected with serotype 3 (serotypes are here described using the proposed consensus nomenclature [23]). Two

Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies

Background and aims: Steatosis, a frequent histological finding in patients with chronic hepatitis C (CHC), has been suggested to influence liver fibrosis progression. The aim of the present study was to evaluate in patients with CHC and paired liver biopsies the relationship between the evolution of steatosis and that of fibrosis between the two biopsies. Methods: Ninety six patients were selected according to the following criteria: absence of treatment; absence of cirrhosis at initial biopsy; and serum hepatitis B surface antigen and human immunodeficiency virus antibody negativity. Degrees of necroinflammatory activity, fibrosis, and steatosis grades were assessed in the two biopsies. In addition to histological lesions, parameters studied included the source of infection, duration of infection, body mass index, alcohol intake, alanine aminotransferase levels, hepatitis C virus genotype, and viral load. Results: The mean interval between the two biopsies was 48 (32) months. Steatosis was found in 54% of patients at first biopsy, and was severe in 9%. Worsening of steatosis was observed in 34% of patients, stability in 50%, and improvement in 16%. Worsening of steatosis was significantly associated with hepatic fibrosis progression in patients with (p=0.03) or without (p<0.03) steatosis at diagnosis. Overall, fibrosis progression was observed in 31% of patients and stability in 69%. In a univariate analysis, fibrosis progression was associated with male sex (p=0.05), worsening of histological activity (p=0.04), and worsening of steatosis (p=0.0003). In a multivariate analysis, the only factor independently associated with fibrosis progression was worsening of steatosis (worsening v improvement/stability: odds ratio 4.7 (95% confidence interval 1.3–10.8); p=0.0001). Conclusions: Our results suggest that in untreated patients with CHC and serial liver biopsies, fibrosis progression is strongly associated with worsening of steatosis.

Laparoscopic Liver Resection for Peripheral Hepatocellular Carcinoma in Patients With Chronic Liver Disease: Midterm Results and Perspectives

Objective:Report the midterm results of laparoscopic resection for hepatocellular in chronic liver disease (CLD). Summary Background Data:Surgical resection for hepatocellular carcinoma (HCC) in chronic liver disease (CLD) remains controversial because of high morbidity and recurrence rates. Laparoscopic resection of liver tumors has recently been developed and could reduce morbidity. Methods:From 1998 to 2003, patients with HCC and CLD were considered for laparoscopic liver resection. Inclusion criteria were chronic hepatitis or Childs A cirrhosis, solitary tumor ≤5 cm in size, and location in peripheral segments of the liver. Mortality, morbidity, recurrence rates, and survival were analyzed. Results:A total of 27 patients were included. Liver resections included anatomic resection in 17 cases and non anatomic resection in 10. Seven conversions to laparotomy (26%) occurred for moderate hemorrhage in 5 cases and technical difficulties in 2 cases. Mortality and morbidity rates were 0% and 33%, respectively. Postoperative ascites and encephalopathy occurred in 2 patients (7%) who both had undergone conversion to laparotomy. Mean surgical margin was 11 mm (range, 1–47 mm). After a mean follow-up of 2 years (range, 1.1–4.7), 8 patients (30%) developed intrahepatic tumor recurrence of which one died. Treatment of recurrence was possible in 4 patients (50%), including orthotopic liver transplantation, right hepatectomy, radiofrequency ablation, and chemoembolization in 1 case each. There were no adhesions in the 2 reoperated patients. Overall and disease-free 3-year survival rates were 93% and 64%, respectively. Conclusion:Our study shows that laparoscopic liver resection for HCC in selected patients is a safe procedure with very good midterm results. This approach could have an impact on the therapeutic strategy of HCC complicating CLD as a treatment with curative intent or as a bridge to liver transplantation.

Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C

Cannabinoids present in Cannabis sativa (marijuana) exert biological effects via cannabinoid receptors CB1 and CB2. We recently demonstrated that CB1 and CB2 receptors regulate progression of experimental liver fibrosis. We therefore investigated the impact of cannabis smoking on fibrosis progression rate in patients with chronic hepatitis C (CHC). Two hundred seventy consecutive untreated patients with CHC of known duration undergoing liver biopsy were studied. Demographic, epidemiological, metabolic, and virological data were recorded, and detailed histories of cannabis, alcohol, and tobacco use over the span of hepatitis C virus infection were obtained. Fibrosis stage, steatosis, and activity grades were scored according to Metavir system. Patients were categorized as noncannabis users (52.2%), occasional users (14.8%), or daily users (33.0%), and the relationship between cannabis use and fibrosis progression rate (FPR) or fibrosis stage was assessed. On multivariate analysis, six factors were independently related to a FPR greater than 0.074 (median value of the cohort): daily cannabis use (OR = 3.4 [1.5‐7.4]), Metavir activity grade A2 or higher (OR = 5.4 [2.9‐10.3]), age at contamination of more than 40 years (OR = 10.5 [3.0‐37.1]), genotype 3 (OR = 3.4 [1.5‐7.7]), excessive alcohol intake (OR = 2.2 [1.1‐4.5]), and steatosis (OR = 2.0 [1.0‐4.1]). Daily cannabis use was also an independent predictor of a rapid FPR (>0.15) (OR = 3.6 [1.5‐7.5]). Finally, severe fibrosis (≥F3) was also predicted by daily cannabis use (OR = 2.5 [1.1‐5.6]; P = .034), independently of Metavir activity grade, excessive alcohol intake, age at liver biopsy, steatosis, and tobacco smoking. In conclusion, daily cannabis smoking is significantly associated with fibrosis progression during CHC. Patients with ongoing CHC should be advised to refrain from regular cannabis use. (HEPATOLOGY 2005;.)

Impact of pretransplantation transarterial chemoembolization on survival and recurrence after liver transplantation for hepatocellular carcinoma.

The actual impact of transarterial chemoembolization before liver transplantation (LT) for hepatocellular carcinoma (HCC) on patient survival and HCC recurrence is not known. Between 1985 and 1998, 479 patients with HCC in 14 French centers were evaluated for LT. Among these 479 patients, this case‐control study included 100 patients who received transarterial chemoembolization before LT (TACE group) and 100 control patients who did not receive chemoembolization (no‐TACE group). Patients and controls were matched for the pre‐LT tumor characteristics, the period of transplantation, the time spent on the waiting list, and pre‐ and posttransplantation treatments. Kaplan‐Meier estimates were calculated 5 years after LT and were compared with the log‐rank test. The mean waiting time before LT was 4.2 ± 3.2 months in the TACE group and 4.3 ± 4.4 months in the no‐TACE group. The median number of TACE procedures was 1 (range: 1‐12). Demographic data, median alpha‐fetoprotein level (21.6 ng/mL and 22.0 ng/mL, respectively), and pre‐ and post‐LT morphologic characteristics of the tumors did not differ in the TACE and no‐TACE groups. Overall 5‐year survival was 59.4% with TACE and 59.3% without TACE (ns). Survival rates did not differ significantly between the two groups with respect to the time on the waiting list, the tumor diameter, or the type of TACE (selective or nonselective). In the TACE group, 30 patients had tumor necrosis ≥80% on the liver explant with a 5‐year survival rate of 63.2%, compared with 54.2% among their matched controls (P = 0.9). In conclusion, with a mean waiting period of 4.2 months and 1 TACE procedure, pre‐LT TACE does not influence post‐LT overall survival and disease‐free survival. (Liver Transpl 2005;11:767–775.)

Oral contraceptive use and focal nodular hyperplasia of the liver

BACKGROUND & AIMS Because most patients with focal nodular hyperplasia (FNH) are young women, an important decision is whether to discontinue oral contraceptive (OC) use. The aims of this study were to evaluate (1) the number and size of FNH lesions in women with various patterns of OC use and in women without OC use and (2) the modifications in the number and size of FNH lesions during follow-up, according to OC use. METHODS In a 9-year study in 216 women with FNH, the diameter and number of lesions documented by magnetic resonance (MR) imaging were evaluated (1) at diagnosis according to OC use as follows: group A, no OC use (n = 28); group B, high-dose OC use (n = 46); group C, low-dose OC use (n = 98); group D, successive use of high-dose and low-dose OCs (n = 33); and group E, use of progestogens only (n = 11); and (2) during follow-up in 136 women, 14 of whom were OC nonusers who stayed off OCs, 89 discontinued OC use, 26 took low-dose OCs, and 7 stayed on a progestogen only. Twelve women became pregnant. In 168 women, the diagnosis of FNH was made based on a combination of rigorously defined MR criteria. In the remaining 48 patients, diagnosis was by surgical biopsy (n = 36) or resection (n = 12). Mean diameter and number of lesion(s) per patient were assessed by MR imaging using the same protocol in all study patients. RESULTS No significant differences in the number or size of lesions were found in the 5 patient groups. During follow-up, a change in lesion diameter occurred in only 4 women; this event was not influenced by OC use. In the 12 patients who became pregnant, lesion size was unchanged after delivery, pregnancy was uneventful, and delivery occurred spontaneously. CONCLUSIONS These data suggest that (1) neither the size nor the number of FNH lesions are influenced by OC use; (2) size changes during follow-up are rare and do not seem to depend on OC use; and (3) pregnancy is not associated with FNH changes or complications.