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Current Issue

October - December, 2008

Vol. 7 Issue 4

On the cover: Official Journal of the Mexican Association of Hepatology and the Latin-American Association for the Study of the Liver

HEPATOLOGY HIGHLIGHTS

CONCISE REVIEW

  • Hepatic hydrothorax: Current concepts of pathophysiology and treatment options Camron Kiafar, Nooman Gilani Page 313-320

    Pleural effusions develop in 6-10% of patients with endstage liver disease. Although, commonly seen in conjunction with ascites, isolated hepatic hydrothorax can occur in a small number of patients with cirrhosis. Refractory hepatic hydrothorax particularly poses a challenging therapeutic dilemma as treatment options are limited at best in these patients. Current pathophysiologic understanding of this disorder, as a cause, points towards the presence of diaphragmatic defects responsible for the shift of fluid from the peritoneal to the pleural cavity. When sodium restriction and diuretic treatment fail, liver transplantation remains the most definitive therapy in these refractory cases. However, transjugular intrahepatic porto-systemic shunt (TIPS), or video-assisted thoracoscopic (VATS) repair of the diaphragmatic defects (with or without pleurodesis) are effective strategies in those who are not transplant candidates or those awaiting organ availability. Hepatic hydrothorax, especially when refractory to medical treatment, poses a challenging management dilemma. An early recognition and familiarity with available treatment modalities is crucial to effectively manage this exigent complication of cirrhosis.

  • Portopulmonary hypertension: state of the art Mateo Porres-Aguilar, Marc J. Zuckerman, Juan B. Figueroa-Casas, Michael J Krowka Page 321-330

    Portopulmonary hypertension is an uncommon but treatable pulmonary vascular consequence of portal hypertension, which can lead to significant morbidity and mortality. Portopulmonary hypertension results from excessive pulmonary vasoconstriction and vascular remodeling that eventually leads to right-heart failure and death if left untreated. Although pulmonary vascular disease in these patients may be asymptomatic or associated with subtle and nonspecific symptoms (dyspnea, fatigue and lower extremity swelling), it should be looked for especially if patients are potential candidates for liver transplantation. Patients with clinical suspicion of portopulmonary hypertension should undergo screening testing, specifically echocardiography. Right heart catheterization remains the gold standard for the diagnosis. The existence of moderate to severe disease poses higher risks and challenges for liver transplantation. The disease has a substantial impact on survival and requires focused pharmacological therapy. New and evolving medical therapies, such as prostanoids (intravenous, inhaled or oral), endothelin receptors antagonists, phosphodiesterases inhibitors, combination therapy and other experimental drugs might change the natural course of the disease. Case reports and cases series have been published regarding the efficacy and safety of pharmacological therapy, but randomized, controlled multicenter trials are urgently needed. Liver transplantation is not the treatment of choice for portopulmonary hypertension, but after optimal hemodynamic and clinical improvement with medical therapy as a bridge, liver transplant can be considered an option in selected patients.

ORIGINAL ARTICLES

  • Acute renal failure induced by carbon tetrachloride in rats with hepatic cirrhosis Fernando Jaramillo-Juárez, María Luisa Rodríguez-Vázquez, Ana Rosa Rincón-Sánchez, María Consolación Martínez, Genaro G. Ortiz, Javier Llamas, Francisco Anibal Posadas, José L Reyes Page 331-338

    Relationship between cirrhosis and renal dysfunction is not yet fully understood. A model of cirrhosis with acute hepatic and renal damage (RF), produced by CCl4 in rats, with hemodynamic and renal functional alterations, similar to those observed in decompensated cirrhosis (DC) in man, was used to study chemical nephrotoxicity in animals. We performed in male Wistar rats hepatic and renal functional and hemodynamic studies in control, cirrhotic and decompensated cirrhotic (DC) groups. Cirrhosis was induced with carbon tetrachloride by chronic administration. Association between liver and renal functional alterations was detected in rats with decompensated cirrhosis, showing fall in mean arterial pressure and reduction of glomerular filtration rate and filtration fraction. Renal hemodynamics did not change in cirrhotic rats, similarly to what occurs in compensated cirrhotic patients. However, DC rats exhibited increased sodium, glucose and phosphate urinary excretions and decreased ATP in renal cortex. DC animals had severe hypoglycemia. There was an extensive liver fibrosis. Glomeruli had hypercellularity and tubules showed extensive vacuolization in cirrhotic and DC rats. The present study suggests that in this model, damage typical of acute tubular necrosis ensues in cirrhotic rats. We describe functional and morphological damage in liver and kidney in a model of cirrhosis that might predispose to the development of acute renal failure when an individual with hepatic damage is exposed in acute way to chemical toxicants.

  • Detection of p53 codon 249 mutation in Nigerian patients with hepatocellular carcinoma using a novel evaluation of cell-free DNA Rufina Igetei, Jesse A. Otegbayo, Dennis A. Ndububa, Olufunmilayo A. Lesi, Chiaka I. Anumudu, Pierre Hainaut, Emmanuelle Gormally Page 339-344

    Objectives: This case-control study was done to determine the association and prevalence of p53 codon 249 mutation using cell-free DNA in the plasma of patients with hepatocellular carcinoma (HCC) in South-Western Nigeria. Method: Eighty-five adults with HCC and seventy-seven age and gender matched controls without evidence of liver disease or malignancy involving any part of the body, were recruited. Plasma DNA was analyzed for p53 codon 249 by restriction fragment length polymorphism. Patient evaluation was done by means questionnaire interview, clinical examination, laboratory and radiological tests. The prevalence of the p53 codon 249 mutation was expressed as a percentage amplifiable DNA samples analyzed from HCC patients while that of controls was expressed in the same way. Fisher's exact test or the student t-test where appropriate were used to assess statistical significance of prevalence between both groups as well as comparison of some characteristics in the HCC cases between those who had codon 249 mutation and those who did not. Associations between the various parameters assessed were determined by odds ratio and significant difference was specified at p < 0.05. Results: p53 codon 249 mutation was present in 6 (7.6%) of the 79 samples from the HCC patients with amplifiable plasma DNA while none (i.e. 0%) of the 73 samples with amplifiable plasma DNA from the controls had this mutation. This prevalence is significantly higher among HCC patients than controls (0.029). The mutation was also found to be significantly associated with HCC (odds ratio = 2.00; 95% C I: 1.70 – 2.35). Conclusion: The prevalence of the p53 codon 249 mutation from plasma DNA of hepatocellular carcinoma patients is significantly higher than among controls in South-Western Nigeria and the presence of this mutation is significantly associated with HCC in this region.

  • Distribution of hepatitis C virus genotypes, risk factors and liver disease in patients from Yucatán, México Beatriz María García-Montalvo, Pedro Luis Galguera-Colorado Page 345-349

    Aim: To make a preliminary determination of hepatitis C virus (HCV) genotype prevalence and possible genotype associations with risk factors and severity of associated liver disease in patients from Yucatan, Mexico. Methods: Sera from 54 patients with positive anti- HCV and HCV RNA were genotyped using reverse transcription-polymerase chain reaction. Risk factors were evaluated using a questionnaire. The evaluations also included serum ALT levels and liver biopsies in some participants. Results: HCV genotype 1 was detected in 37%, genotype 2 in 33.3%, genotype 3 in 16.7% and mixed genotypes in 7.4%. Subtype 2b was the most frequent (33.3%), followed by 1b (18.5%), 3a (16.7%) and 1a (14.8%). Surgeries (53.7%) and transfusion (38.9%) were the main risk factors. Liver biopsies were available in 24 (44.4%) patients. Severe liver disease was present in 6 (54.5%) of the patients with genotype 1 and in none of those with genotype 2. A statistically significant association was observed between patients with a family history of liver disease and genotype 2 (P = 0.021). Liver damage severity increased with longer duration of infection (P = 0.007). No statistically significant association was observed between severe liver damage and the different genotypes. Conclusion: Subtype 2b was the most prevalent. This contrasts with the studies done in different states of Mexico in that this subtype was not identified or had prevalence approximately 2 times less than reported here.

  • AST to platelet ratio index (APRI) for the noninvasive evaluation of liver fibrosis Aurora Loaeza-del-Castillo, Francisco Paz-Pineda, Edgar Oviedo-Cárdenas, Francisco Sánchez-Avila, Florencia Vargas-Vorácková Page 350-357

    Liver biopsy is the recognized gold standard for liver fibrosis staging. The aspartate aminotransferase to platelet ratio index (APRI) has been proposed as a noninvasive and readily available tool for the assessment of liver fibrosis in chronic hepatitis C (CHC). This study aimed to validate, in a Mexican tertiary health care setting, the diagnostic usefulness of APRI in CHC, nonalcoholic fatty liver disease (NAFLD) and autoimmune hepatitis (AIH). In an observational, cross-sectional, comparative and retrolective fashion, consecutive patients with CHC, NAFLD or AIH were evaluated. Fibrosis was staged using the METAVIR scale. Receiver operating characteristic ROC curves were constructed for significant fibrosis, advanced fibrosis and cirrhosis. One-hundred-sixty-four CHC, 30 NAFLD and 42 AIH patients were evaluated. For the diagnosis of significant fibrosis, APRI values delimited an area under de ROC curve (AUC) of 0.776 in CHC, 0.564 in NAFLD, and 0.602 in AIH patients. For advanced fibrosis, the AUCs were 0.803, 0.568 and 0.532 in CHC, NAFLD and AIH patients, respectively. For cirrhosis, AUCs were 0.830 and 0.599 in CHC and AIH patients. In conclusion, APRI can be a useful noninvasive alternative for the diagnosis of significant fibrosis and cirrhosis in our CHC patients. APRI values of ≤ 0.3 and ≤ 0.5 rule out significant fibrosis and cirrhosis, and a value of ≥ 1.5 rules in significant fibrosis. In patients with NAFLD, APRI values tend to increase with the degree of fibrosis, suggesting that it could be useful in this disease. APRI appears to be of no value in patients with AIH.

  • Phytopharmacological evaluation of Byesukar for hypoglycaemic activity and its effect on lipid profile and hepatic enzymes of glucose metabolism in diabetic rats C. Guruvayoorappan, G. Sudha Page 358-363

    Many anti-diabetic herbal preparations have been recommended in alternative systems of medicine for the treatment of diabetes. No systematic study has been done on the anti-diabetic efficacy of Byesukar, a polyherbal formulation to treat diabetes. The anti-diabetic efficacy of byesukar ethanol extract was evaluated in an animal model of diabetes induced by alloxan. Male Wistar rats were divided in to four groups. Group 1 was normal control group; group 2 and 3 received alloxan. After inducing experimental diabetes group 2 served as diabetic control; group 3 received byesukar (500 mg/kg body weight) orally for 30 consecutive days. Group 4 were normal rats which received byesukar extract alone. The effect of byesukar on glucose level in diabetic rats was studied and the level of glucose metabolizing enzymes (Hexokinase, glucose-6- phosphatase and fructose 1, 6-bisphosphatase) in the liver and kidney were estimated. The effect of byesukar on the serum and tissue lipid profile (Cholesterol, triglycerides, phospholipids and free fatty acids) were also estimated in diabetic rats. Our results indicate that treatment with byesukar resulted in significant reduction of blood glucose, tissue glucose-6-phosphatase and fructose 1, 6- bisphosphatase activity. The decreased tissue hexokinase activity in diabetes state was found to be significantly increased by byesukar treatment. Also the byesukar treated diabetic rats showed a significant decrease in the tissue lipid profile compared to the diabetic rats. In conclusion the decreased blood glucose accompanied with decreased lipid profile and changes in the activities of the glucose metabolizing enzymes shows the antidiabetic effect of byesukar.

  • Nonalcoholic fatty liver disease in severely obese individuals: The influence of bariatric surgery Antônio Ricardo de Andrade, Helma P. Cotrim, Erivaldo Alves, Daniela Soares, Raquel Rocha, Alessandro Almeida, Carolina G. Almeida, Luiz Antonio de Freitas Page 364-368

    Background: Obesity is the most frequent risk factor associated with NAFLD, and bariatric surgery (BAS) is traditionally indicated for the treatment of severely obese individuals. Here, we discuss the behavior and prognosis of this liver disease following post-surgical weight loss. Aim: To evaluate the influence of the BAS on the clinical and biochemical parameters of NAFLD in severely obese patients. Methodology: An intervention study included obese individuals (BMI≥ 35kg/m2), who had been submitted to liver biopsy during BAS and had NAFLD. HAIR (hypertension, ALT and insulin resistance and BAAT (BMI, ALT, age and triglycerides) scores and FLI (Fatty Liver Index) were used to compare the patients at the time of surgery, and 12-30 months following weight loss. Results: From October 2004 to September 2007, 122 patients were diagnosed with NAFLD, 40 of whom agreed to participate in the study. The mean age was 37.7 ± 12.5 years, 60% were women and 80% had steatohepatitis (NASH) with fibrosis upon analysis of the liver biopsy performed during BAS. Mean weight loss was 46.0 ± 2.0 kg. After 21 ± 5.8 months of follow-up, a significant improvement was found in all the variables analyzed (79.3% according to the HAIR scores, 95.2% as measured by the BAAT score and 72.5% by the FLI. Conclusion: The results suggest that treatment of obesity by bariatric surgery may influence the prognosis of NAFLD. In addition to weight loss, we observed improvement in the clinical and biochemical parameters related to NAFLD, such as anthropometrics index, hypertension, aminotransferases, triglycerides and insulin resistance.

  • Efficacy of triple therapy with thymalfasin, peginterferon Alpha-2a, and ribavirin for the treatment of hispanic chronic HCV nonresponders Jorge L. Poo, Francisco Sánchez-Avila, David Kershenobich, Xochitl García Samper, Rocío Torres-Ibarra, Julieta Góngora, Carlos Cano, Miguel Parada, Misael Uribe Page 369-375

    Background/Aims: Thymalfasin has shown efficacy in the treatment of chronic HCV infection. The aim of this study was to evaluate the efficacy and tolerability of triple therapy with thymalfasin, peginterferon α-2a (PEG-IFN α-2a), and ribavirin in Hispanic patients with chronic viral hepatitis C who were nonresponders to prior treatment with interferon alfa (IFN-α)/ribavirin. Methods: In this open-label study, 40 subjects received thymalfasin (1.6 mg twice a week), PEG-IFN α- 2a (180 μg once a week), and ribavirin (800-1,000 mg/ day) for 48 weeks. All patients had positive HCV RNA by PCR analysis, abnormal levels of ALT, compensated hepatic disease, and liver biopsy with chronic damage. Results: Viral response was observed in 52.5% patients at week 12 and 50% at week 24. Of the per protocol group, 52.6% showed an end-of-treatment response at week 48 and 21.1% achieved an SVR at week 72. Among genotype 1 patients, 23.5% achieved an SVR at week 72. A reduction of the dose of PEG IFN α-2a and ribavirin was required. Thymalfasin was well tolerated without dose reduction. Conclusion: Triple therapy with thymalfasin, PEG IFN α-2a, and ribavirin is an effective treatment option for difficult-to-treat HCV patients who are refractory to prior conventional treatment, with adequate tolerability.

  • Mycophenolate mofetil in liver transplant patients with calcineurin-inhibitor-induced renal impairment Hin Hin Ko, Erica Greanya, Tim K Lee, Urs P. Steinbrecher, Siegfried R. Erb, Eric M. Yoshida Page 376-380

    Background: Calcineurin inhibitors (CNIs) provide effective immunosuppression after orthotopic liver transplantation (OLTx), but the associated nephrotoxicity can cause substantial morbidity and mortality among transplant patients. In this study, we retrospectively investigated the efficacy and safety of mycophenolate mofetil (MMF) in OLTx patients with CNI-induced renal impairment. Patients & Methods: A chart review was undertaken of all liver transplant recipients followed at the Vancouver General Hospital. Twenty-one (12 male) patients were converted to either MMF monotherapy (n = 18) or MMF with corticosteroids (n = 3) for CNI-induced renal dysfunction. Six were excluded because of other factors contributing to renal dysfunction. Mean time from OLTx to conversion was 11.3 years and mean age was 60. Non-parametric Wilcoxon's signed rank testing was used to determine whether there was a difference between the serum creatinine (SCr) before conversion, and 3 or 6 months after conversion. Results: Median follow-up was 294 days, ranging from 35 to1103 days. The median SCr was significantly reduced from 144 μmol/L before conversion to 129 μmol/L and 139 μmol/L at 3 and 6 months follow-up (p = 0.001 and 0.008, respectively). MMF was well tolerated. Only one patient (6.7%) had elevated liver enzymes and required addition of sirolimus while two (13.4%) experienced gastrointestinal intolerance. Conclusions: MMF appears to be safe for stable OLTx recipients with CNI-induced nephrotoxicity. Serious side effects were uncommon as only one patient required discontinuation of the medication. However, longer follow-up and larger study populations are needed in the future to better determine its efficacy and safety.

IMAGES IN HEPATOLOGY

CASE REPORTS

  • Multinodular fatty liver after herpes-zoster vaccine: Case report and review of the literature Michael Shim, Francisco Durazo Page 382-385

    Multinodular fatty liver (MNFL) is a pattern of fatty infiltration of the liver characterized by multiple wellcircumscribed nodules on hepatic imaging, often raising the concern of metastatic malignancy. Here we describe a case of MNFL and review the published literature. There is likely some association between traditional risk factors for hepatic steatosis (e.g. alcohol, rapid weight change, metabolic syndrome, medications, TPN) and MNFL. Further study and reporting of cases of MNFL are needed to better characterize its pathogenesis and natural history.

  • Subcapsular liver hematoma after endoscopic retrograde cholangiopancreatography in a liver transplant recipient Cárdenas Cárdenas, Gonzalo Crespo, Domingo Balderramo, Josep M. Bordas, Oriol Sendino, Josep Llach Page 386-388

    Endoscopic Retrograde Cholangiopancreatography (ERCP) is commonly performed in patients after liver transplantation. The most common indications for ERCP include treatment of bile leaks and anastomotic and nonanastomotic biliary strictures. In this report we describe an unusual complication of ERCP in a liver transplant recipient with a bile leak two months after orthotopic liver transplantation (OLT). After confirming a bile leak, a hydrophilic guide wire was placed in the intrahepatic duct, an endoscopic sphincterotomy was performed, and a biliary plastic stent was successfully placed over the wire across the bile leak. Within the following 24 hours the patient developed a sharp right-sided upper quadrant pain and a drop in his hemoglobin level. An abdominal CT scan demonstrated a subcapsular hepatic hematoma that was successfully managed conservatively.

LETTER TO EDITOR

LIVER NEWS ELSEWHERE

  • Optimizing dosage and duration therapy for chronic hepatitis C «difficult-to-treat patients» José M. Ladero Page 392-394

    Treatment response remains suboptimal for many patients with chronic hepatitis C, particularly those with genotype 1 and high levels of viremia. The efficacy of high-dose regimens of peginterferon α-2a and ribavirin was compared with conventional dose regimens in patients with features predicting poor treatment responses. Eligible treatment-naïve adults with genotype 1 infection, hepatitis C virus (HCV) RNA > 800,000 IU/ mL and body weight > 85 kg were randomized to double- blind treatment with peginterferon α-2a at 180 or 270 microg/week plus ribavirin at 1,200 or 1,600 mg/ day for 48 weeks (four regimens were evaluated). The primary endpoint was viral kinetics during the first 24 weeks of therapy. Among patients receiving peginterferon α-2a (270 microg/week) the magnitude of HCV RNA reduction was significantly greater than for patients randomized to the conventional dose of peginterferon α-2a (180 microg/week) for the pairwise comparison for ribavirin at 1,600 mg/day (P = 0.036) and numerically greater for the pairwise comparison for ribavirin at 1200 mg/day (P = 0.060). Patients randomized to the highest doses of peginterferon α-2a (270 microg/week) and ribavirin (1,600 mg/day) experienced the numerically highest rates of sustained virologic response (HCV RNA < 50 IU/mL) and the lowest relapse rate (47% and 19%, respectively). The arm with the higher doses of both drugs was less welltolerated than the other regimens. Conclusion: Higher fixed doses of peginterferon alfa-2a (270 microg/ week) and ribavirin (1600 mg/day) may increase sustained virologic response rates compared with lower doses of both drugs in patients with a cluster of difficult- to-treat characteristics.

The Official Journal of the Mexican Association of Hepatology, the Latin-American Association for the Study of the Liver and the Canadian Association for the Study of the Liver

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