Recent attention has focused on the liver profibrogenic role of leptin in animal models. The purpose of this study was to evaluate the role of leptin and TNF-alpha in the severity of liver fibrosis in patients with chronic hepatitis C (CHC).

French researchers used a radioimmunoassay to determine serum leptin concentrations in 77 consecutive patients with CHC and 22 healthy controls. Leptin was correlated with liver histological (METAVIR) and metabolic indices.

Study Results

Sixty five patients had none to moderate liver fibrosis (F0-F2) and twelve [had] severe fibrosis (F3-F4). Steatosis was observed in all but 27 patients. Leptin was significantly increased in patients compared with controls and was significantly more elevated in females both in patients and controls. The age, age at infection, prothrombin index, body mass index (BMI), triglycerides, glycaemia, ferritin, leptin and TNF-alpha, were associated with severe fibrosis.

Steatosis was significantly more pronounced in patients with severe fibrosis than those without or moderate fibrosis (P = 0.04).

Only leptin was significantly and independently associated with severe fibrosis. Leptin was significantly associated with BMI (r = 0.64, P < 0.001) and glycaemia (r = 0.43, P < 0.001).

Significant correlations were found between steatosis and BMI (r = 0.30, P < 0.01) and glycaemia (r = 0.30, P < 0.01).

The authors conclude, “In patients with CHC and higher BMI and glycaemia levels, the severity of liver fibrosis is associated with serum leptin. TNF-alpha is a putative candidate involved in the mechanism.”

Department of Hepatogastroenterology Department of Pathology Department of Biochemistry Department of Virology Department of Immunology, CHU de NICE, France.

02/02/04

Reference
T Piche and others. The severity of liver fibrosis is associated with high leptin levels in chronic Hepatitis C. Journal of Viral Hepatitis 11(1): 91-6. January 2004.

Surgical samples of livers from patients with chronic hepatitis C were studied. Measurement of fibrosis was performed on the whole section by using both image analysis and METAVIR score (reference value). From the digitized image of the whole section, virtual biopsy specimens of increasing length were produced. Fibrosis was assessed independently on each individual virtual biopsy specimen. Results were compared with the reference value according to the length of the biopsy specimen.

By using image analysis, the coefficient of variation of fibrosis measurement with 15-mm long biopsy specimens was 55%; and for biopsy specimens of 25-mm length it was 45%. By using the METAVIR scoring system, 65% of biopsies 15 mm in length were categorized correctly according to the reference value. This increased to 75% for a 25-mm liver biopsy specimen without any substantial benefit for longer biopsy specimens.

Sampling variability of fibrosis is a significant limitation in the assessment of fibrosis with liver biopsy.

The authors conclude, “This study suggests that a length of at least 25 mm is necessary to evaluate fibrosis accurately with a semi-quantitative score. Sampling variability becomes a major limitation when using more accurate methods such as automated image analysis.”

Service d'Anatomie Pathologique, Hopital Bicetre, Le Kremlin-Bicetre, France.

01/19/04

Reference
P Bedossa and others. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 38(6): 1449-57. December 2003.

Long-term Outcome (35 years) of Hepatitis C After Acquisition of Infection Through Mini Blood Transfusions Given at Birth

Long-term follow up studies of hepatitis C virus (HCV) infection rarely exceed 20-25 years. Italian researchers studied the outcome of HCV infection in 35-yr-old adults infected at birth (1968) through mini transfusions of blood.

A retrospective-prospective study was carried out. The cohort included 31 individuals who were given mini blood transfusions (21-30 ml) collected from a donor subsequently revealed to be HCV-infected. At enrollment (1998), 18 of 31 (58.1%) recipients had anti-HCV antibody and 16 (88.9%) of them were HCV-RNA positive. All viremic recipients and the infectious donor had the same genotype 1b.

Sequence analysis of E1/E2 and NS5b regions, coupled with phylogenetic analysis, indicated that HCV isolates from donor/recipients were linked. Eleven of the 16 viremic recipients gave consent to liver biopsy. Nine had no fibrosis or mild portal fibrosis and 2 had either discrete (Ishak's staging 3) or marked (Ishak's staging 4) fibrosis.

During the prospective follow-up period (1998-2003), 2 patients were given therapy, one of whom achieved sustained clinical and virologic response. A second biopsy, performed in 5 patients at a 5 yr interval, revealed no substantial modifications in 4 cases and progression from absence of fibrosis to mild portal fibrosis in the fifth.

In conclusion, the authors note, “Taking into account the limited study sample, these findings suggest that HCV infection acquired early in life shows a slow progression and mild outcome during the first 35 years of infection.”

Liver Unit, Department of Medicine, Hospital of Legnano, Milan, Italy.

 

02/27/04

Reference
MA Casiraghi and others. Long-term outcome (35 years) of hepatitis C after acquisition of infection through mini transfusions of blood given at birth. Long-term outcome (35 years) of hepatitis C after acquisition of infection through mini transfusions of blood given at birth. Hepatology 39(1): 90-96. January 2004.

Daily Cannabis Smoking as a Risk Factor for Fibrosis Progression in Chronic Hepatitis C
 

A French research group reported results from this study at EASL (April 14-18, 2004, Berlin, Germany).
 
C. Hezode^{1}, F. Roudot-Thoraval ^{2}, P. Grenard ^{3}, B. Julien ^{3}, E.S. Zafrani ^{4}, D. Dhumeaux ^{1}, S. Lotersztajn ^{3}, A. Mallat ^{1} ^{3}; ^{1}Department of Hepatology, Hopital Henri Mondor, Creteil, France; ^{2}Department of Public Health, Hopital Henri Mondor, Creteil, France; ^{3}INSERM U581, Hopital Henri Mondor, Creteil, France; ^{4}Department of Pathology, Hopital Henri Mondor, Creteil, France
 
AUTHOR'S CONCLUSIONS: This study shows a strong link between daily cannabis consumption and fibrosis progression rate in patients with chronic hepatitisC. These results support experimental data demonstrating the profibrogenic role of CB1 receptors, see below (Grenart et al). Daily cannabis consumption should be avoided in patients with chronic hepatitis C. In multivariate analysis, fibrosis progression rate >0.08 U per year was independently related to a 4 times greater risk from daily cannabis smoking; alcohol intake _30 grams/day showed double the risk for faster fibrosis progression; age at contamination >24 years was associated with a 4 times greater risk for faster fibrosis progression; and activity _A2 was associated with 7 times greater risk for faster fibrosis progression. Pharmacologic antagonists of CB1 receptors may represent a new approach in the treatment of liver fibrosis.
 
Note from Jules Levin: Interestingly, Diana Sylvestre found in study that smoking marijuana increased sustained viral response rates of patients on Methadone Maintenance. The suggestion is that smoking pot may have improved adherence and tolerability of interferon/ribavirin therapy.
 
Several host, viral and environmental factors modulate development of fibrosis in patients with chronic hepatitis C. Progression may occurin the absence of risk factors.
 
Cannabis sativa, also known as marijuana, contains a predominant psychoactive cannabinoid, tetrahydrocannabinal (THC) and over 60 other cannabinoid compounds.
 
Biological effects of THC and other cannabinoids are mediated by 2 types of receptors CB1 and CB2.
 
Study authors said we recently demonstrated the profibrogenic role of CB1 receptors (P Grenard et al):
 
---CB1 receptors are highly upregulated in hepatic myofibroblasts of human cirrhotic liver samples
 
---following chronic tetrachloride administration, CB1 knock out mice showreduced fibrosis compared to wild type mice
 
The AIM OF THIS STUDY is to evaluate the impact of cannabis smoking on fibrosis progression rate in patients with chronic hepatitis C.
 
PATIENTS
--211 consecutive naïve patients with histologically proven chronic hepatitis C
--known disease duration
--no HBV or HIV coinfection
--no previous immunosuppression
 
METHODS
 
Epidemiological data:
--gender
--age at exposure, duration og HCV infection
 
Alcohol and tobacco consumption over the course of infection
 
Cannabis questionnaire:
--age at onset and duration of smoking
--amount and frequency of cannabis cigarettes
 
BMI and glucose fasting level
 
Genotype (INNO-LIPA HCV II, innogenetics)
 
Activity, fibrosis, and steatosis: METAVIR
 
ENDPOINTS
 
Fibrosis progression rate (fibrosis stage/duration of infection)
 
--rapid fibrosers: >0.08 U/yrs (median value
 
Significant fibrosis: ≥F2 (METAVIR)
 
CANNABIS CONSUMPTION
 
 

 

 
FIBROSIS STAGE and DAILY CANNABIS SMOKING ACCORDING TO AGE AT LIVER BIOPSY
 
If ≥ 40 yrs old: 58% of DAILY SMOKERS vs 44% of non & occasional smokers had Fibrosis ≥ F2.
 
If <40 yrs old: 23% of non and occasional smokers vs 43% of daily smokers had Fibrosis ≥ F2.
 
FIBROSIS STAGE and DAILY CANNABIS SMOKING ACCORDING TO AGE AT LIVER BIOPSY AND ALCOHOL INTAKE
 
DIFFERENCES SIGNIFICANT
If < 40 yrs old & alcohol <30 grams/day: 20% of non and occasional smokers vs 37% of daily smokers had Fibrosis ≥ F2.
 
If ≥ 40 yrs old & alcohol <30 grams/day: 35% of non and occasional smokers vs 71% of daily smokers had Fibrosis ≥ F2.
 
DIFFERENCES NOT SIGNIFICANT
If Alcohol >30 grams/day and < 40 yrs old: 38% of non and occasional smokers vs 50% of daily smokers had Fibrosis ≥ F2.
 
If Alcohol > 30 grams/day and > 40 yrs old: 76% of non and occasional smokers vs 50% of daily smokers had Fibrosis > F2.
 
www.natap.org

In patients with chronic hepatitis C, sustained virological response (SVR) seems to be associated with a significant decrease in the occurrence of clinical complications. Such an effect has not yet been demonstrated in patients with cirrhosis or advanced fibrosis, as SVR in patients treated with interferon (IFN) monotherapy was very low.

The aim of the present study at the Hopital Jean Verdier in Bondy, France was  to assess the occurrence of clinical events according to virological response in a homogeneous cohort of patients with HCV-related cirrhosis or severe fibrosis treated with antivirals.

Consecutive patients with the following criteria were retrospectively included:

(1)     HCV-related cirrhosis or advanced fibrosis (Metavir score F3 ou F4);

(2)     Absence of clinical complication or HCC previously or at inclusion;

(3)     Absence of HBV or HIV coinfection or alcohol consumption > 80 g/d;

(4)     No contraindication to antiviral treatment;

(5)     Treated by at least one course of antiviral treatment = 3 mo; and

(6)     Regular follow-up = 18 months (US/6 months).

Results

138 patients (mean age: 54±11 years, males: 59%, Metavir F4: 83%, genotype 1: 54%) were included. Treatment courses were performed 1, 2, 3 and 4 times in 45%, 38%, 14% et 3% respectively.

IFN-ribavirin combination therapy was administered in 70%. SVR (negative HCV RNA 6 mos after the end of treatment) was obtained in 53 patients (38%).

SVR and non SVR (NSVR) patients did not differ either in term of follow-up (5.6±2.3 vs 5.7±3.0 years) or of cumulated duration of antiviral treatment (14±6 vs 14±8 months).

Nevertheless, SVR patients were younger (50±11 vs 57±11 yrs, p=0.003), more often belonging to Metavir F3 (28% vs 10%, p<0.01), and less often infected with genotype 1 HCV (41% vs 76%, p<0.0001).

During the follow-up, clinical events occurred in NSVR group but were virtually absent in SVR group (HCC: 22/85 (26%) vs 0/53, p<0.0001 ; decompensation: 10/85 (12%) vs 1/53 (2%), p<0.01).

No patient died in SVR group vs 14/85 in NSVR group (16%, p<0.001); in the latter group, HCC was the cause of death in 43%.

Conclusions

Combination antiviral therapy results in SVR in 38% of patients with HCV-related cirrhosis or advanced fibrosis. Virological cure seems to be associated with a dramatic decrease in the incidence of clinical complications during a mean follow-up period of about 6 years.

“These results are a strong argument for treating and re-treating patients with severe compensated liver disease,” conclude the authors.

04/28/04

Reference
R El Braks and others. EFFECT OF VIRAL CLEARANCE ON CLINICAL OUTCOME IN PATIENTS WITH HCV-RELATED CIRRHOSIS OR ADVANCED FIBROSIS. A RETROSPECTIVE STUDY IN 138 PATIENTS. Abstract 211. 39^th EASL. April 14-18, 2004. Berlin, Germany.

  http://www.hivandhepatitis.com/2004icr/39easl/documents/0428/042804_hcv_h.html

Insulin Resistance, Fibrosis and Genotype Independently Predict the Sustained Response Rate (SVR) to Therapy with Pegylated Interferon Plus Ribavirin

The objectives of the current study, conducted at the University od Valme in Seville, Spain, were to analyze the impact of body composition, leptin system and insulin resistance together with viral factors on sustained viral response in patients with chronic hepatitis C treated with pegylated interferon plus ribavirin (PEG+RIB).

Patients (n=68;male=38;mean age=43+11) with chronic hepatitis C were treated with PEG+RIB. Genotype 1=47 and non-1=21 patients. Fibrosis (F0-F2=47 patients; F3-F4=21). Leptin levels (Quantikyne), insulin levels (ECLIA) and insulin resistance index [HOMA=Insulin (UI/mL) x serum glucose (mmol/L)/22.5] were measured as were BMI and fat distribution.

Results

Patients with SR had a lower BMI (25.7+/-4.2 vs 28.9+/-5.1;p=0.01), were younger (40+/-11 vs 46+/-10), showed lower serum leptin levels (8.43+/-7.33 vs 15.81+/-13.3 ng/ml; p=0.004) and had a lower HOMA (1.9+/-1.1 vs 4.6+/- 2.8; p=0.0001).

SR was achieved in 44.6% genotype 1 versus 90.5% genotype non-1 (p=0.0001),and 74.5%(35/47) in mild fibrosis vs. 23.8%(5/21) in advanced fibrosis(p=0.001).

SR in genotype 1 patients with insulin resistance (HOMA>2) was 23.8% vs 66.6% in genotype 1 patients with normal HOMA; p=0.015.

Neither necroinflammatory activity, nor steatosis, nor HSC activation were associated with SR rate.

The HOMA, fibrosis and genotype were related with the phase 2 in viral dynamics.

In backward logistic multivariate regression analysis, the independent variables related to sustained response were genotype (p=0.001), HOMA (p=0.012) and fibrosis (p=0.029).

In conclusion, the authors write, “Insulin resistance, advanced fibrosis and genotype are independent predictors of the response to antiviral therapy in chronic hepatitis C, and influence the viral dynamics (phase 2) during treatment with pegylated interferon plus ribavirin.”

04/28/04

Reference
M Romero-Gomez and others. INSULIN RESISTANCE, FIBROSIS AND GENOTYPE ARE PREDICTORS OF  SUSTAINED RESPONSE RATE TO PEGYLATED INTERFERON PLUS RIBAVIRIN IN PATIENTS WITH CHRONIC HEPATITIS C. Abstract 508. 39^th EASL. April 14-18, 2004. Berlin, Germany.