Category Archives: Hepatology

Augmentin Hepatotoxicity

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Augmentin (amoxicillin-clavulanic acid) hepatotoxicity is common, anywhere from 1 in 1000 prescriptions to 1 in 78,000 prescriptions.  Despite its frequent use in pediatrics, there is limited data on augmentin hepatotoxicity in this population.  A recent study adds some information (JPGN 2012; 55: 663-67).

As part of a prospective observational study involving 8 Spanish hospitals from 2008 to 2011, 11 patients, ages 1 to 11 years, with augmentin hepatotoxicity were identified.  Drug-induced hepatotoxicity was suspected in the presence of augmentin therapy if ALT was >2 time ULN, conjugated bilirubin was >2 times ULN, or if other liver biochemistries (AST/GGT or bilirubin) were >2 times ULN.  Causality criteria relied on the Council for International Organizations of Medical Sciences (CIOMS) scale.

According to CIOMS scale, 3 cases were highly probable for augmentin hepatotoxicity, 3 cases were probable, and 5 cases were possible.  In this study, the patient’s details and labs are given in Table 1.  Most cases were mild.  The most common symptom was vomiting. Only one had a bilirubin >1 mg/dL.  Two had very high ALT values (one 52 times normal). Viral serology (measured at least 2 determinations) and autoimmune titers were negative in all patients.

Resolution of the hepatotoxicity occurred over a 4 to 16 week period.  No cases required a biopsy.  The authors note that many more cases of milder disease likely go undetected.

Related blog entry:

Reference:

  • -Curr Drug Saf 2010; 5: 212-22.  Antibiotic-induced liver toxicity –clinical features/causality.
  • -JPGN 2008; 47: 395-405.  Drug-related hepatotoxicity/liver failure
  • -J Pediatr 2000; 136: 121.  Augmentin & cholestasis. 1.7 cases per 10,000 prescriptions.

Does NAFLD cause hepatocellular cancer?

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Probably (Clin Gastroenterol Hepatol 2012; 10: 1342-59).

The authors of this study reviewed original reports between 1992-2011 and narrowed them to those with pertinent information regarding evidence of whether non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) contributed to a higher risk of hepatocellular carcinoma (HCC).

17 cohort studies, 18 case-control and cross-sectional studies, and 26 case series were identified.

Results:

  • Cohorts with NASH and cirrhosis had a consistently higher risk of HCC; cumulative risk ranged from 2.4% over seven years to 12.8% over 3 years.
  • Cohorts with few or no cases of cirrhosis had a minimal risk of HCC; cumulative risk of HCC mortality was 0-3% for study periods up to 20 years.

The results of patients with NASH and cirrhosis are in agreement with a recent presentation at AASLD meeting; however, there may be a small risk even in the absence of cirrhosis (Fatty Liver Disease Cited for Rise in Hepatocellular Carcinoma November 2012):

“Of 17,895 HCC cases in the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database, 2,863 (16%) had only NAFLD without any other risk factors or etiologies for HCC. The linked database covers 30% of the U.S. Medicare population. SEER itself contains data from 18 cancer registries covering 28% of the U.S. population.” In addition, “Cirrhosis was not present in 36% of the NAFLD-related HCC cases.” In the SEER database, the odds ratio for developing HCC with cirrhotic NAFLD was 16.5 compared with those with noncirrhotic NAFLD.

Related blog entry:

NAFLD Guidelines 2012 | gutsandgrowth

More on entecavir and tenofovir

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In a previous post (Extended data with entecavir & annotated HBV management …) good news on the long term use of entecavir was reported.  Another large study indicates that  entecavir (ETV) monotherapy generally produces equivalent results to combination therapy with tenofovir (TDF) (Gastroenterol 2012; 143: 619-28).

The authors report their experience with a randomized open-label multi center study with 379 nucleos(t)ide-naive patients; 264 were HBeAg-positive and 115 were HBeAg-negative.  At week 96, among all patients, virology response defined as HBV DNA <50 IU/mL was 76.4% in the ETV group and 83.2% in the ETV-TDF group.

In multiple comparisons, the combination group tended to have better virological response  except in the HBeAg-negative group (91.1% ETV vs. 89.8% in ETV-TDF).  The other comparisons included the HBeAg-positive group (69.8% ETV vs. 80.4% ETV-TDF), low baseline HBV DNA (<10 to the 8th IU/mL) (83% in both groups), and the high baseline HBV DNA (62.0% ETV vs. 78.8% ETV-TDF).  Yet, the only group where this was statistically significant was those with high baseline HBV DNA, n= 164 (>10 to the 8th IU/mL).

Biological response was greater in the ETV monotherapy, 81.9% compared with 69% in the combination group.  Among HBeAg+ patients, loss of e antigen was comparable: 38.9% in ETV compared with 29.7% in ETV-TDF.  In this group, seroconversion to HBeAb+ occurred in 32.5% of ETV compared with 21.7% of combination patients.

Safety: five patients in combination group and two patients in ETV monotherapy group discontinued treatment due to adverse events.  Three deaths occurred in the combination group (either on treatment or during followup), with the following causes: cardiac arrest, bile duct tumor, and liver failure.  In the patient with liver failure, she had responded to therapy but experienced a breakthrough at week 48.  At week 100, she was switched to commercial treatment.  Five days later she was hospitalized and died within 1 week.  No resistance to either drug was identified.  Thus, the authors speculate that nonadherence was an important factor.  Also, during the course of the study, five malignancies were diagnosed, including 3 with HCC.

Vaniprevir for HCV

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Vaniprevir (MK-7009) is a hepatitis C virus (HCV) NS 3/4A protease inhibitor.  A phase II study has shown that vaniprevir can be an effective agent in combination with pegylated interferon alpha-2a (PEG-IFN) and ribavirin (RBV) (Hepatology 2012; 56: 884-93).

This double-blind, placebo-controlled study examined 94 patients with treatment-naive genotype 1 HCV.  In combination with PEG-IFN/RBV, patients received either placebo, vaniprevir 300 mg BID, 600 mg BID, 600 mg QD or 800 mg QD for 28 days & then open-label PEG-IFN/RBV for 44 weeks.  There were 18-20 patients in each group.

With all of these vaniprevir doses, there was a rapid two-phase decline in viral load; the HCV RNA level was approximately 3log10 IU/mL lower in vaniprevir-treated patients than placebo.  Rapid viral response occurred in 68.8-83.3% of vaniprevir-treated patients compared to 5.6% of control patients.  Sustained virologic response was higher but did not reach statistical significance.

Resistance to vaneprevir with variants at R155 and D168 was detected in a small number of patients.  The authors note that treatment outcomes were not related to interleukin-28B genotype.

The potential advantage of vaneprevir over currently available triple therapy agents (eg. telaprevir and boceprevir) would be easier administration, QD or BID, and possibly more favorable side effect profile.

Take home message: more treatment options, including vaneprevir, for HCV are on the horizon.

Related blog posts:

Azathioprine metabolite measurement for Autoimmune Hepatitis

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While obtaining azathioprine (AZA) metabolite levels in inflammatory bowel disease has proven clinical utility, there is less data with regard to autoimmune hepatitis (AIH).  Now a study of 70 adults with AIH reports that therapeutic levels of 6-thioguanine (TGN) (>220 pmol/8 x 10 to the 8th) are associated with remission (Hepatology 2012; 56: 1401-8).

Patients in this study had an average age of 61 years; the average participant had a diagnosis of AIH for 8 years at the start of the study. For induction of remission, patients had received a combination of prednisolone along with AZA.  AZA was started at 1 mg/kg/day and gradually increased to 2 mg/kg/day.  All patients had a complete response to steroids prior to AZA dose escalation.

Outcome from this study was characterized by ability to maintain remission with ALT <33 IU/L and/or relapse which was indicated by ALT >2 x ULN (upper limit of normal) or liver histology showing active disease.

Serial measurements of red blood cell TGN and methylmercaptopurine nucleotides (MeMPNs) were obtained over two years.

Results:

  • 53 patients maintained remission and 17 did not.
  • Those in remission tended to be receiving lower doses of AZA (1.7 vs 2 mg/kg/day) but had higher average TGN levels (237 vs 177 pmol/8 x 10 to the 8th)
  • TGN levels >220 pmol/8 x 10 to the 8th best predicted remission
  • There was no measurable difference in thiopurine methyltransferase (TPMT) activity between the two groups (remission vs relapse).
  • Two patients developed cholestasis and this was associated with high MeMPN levels.

The authors note that several previous studies did not demonstrate a relationship between TGN levels and efficacy.  This is likely related to patient selection (all in remission at start in current study), repeated TGN levels, and the definition of remission.

Conclusion: Obtaining metabolites in adherent patients may be beneficial in patients with active disease to assist with dose modification and in individuals with potential AZA toxicity.

Related blog entries:

Congenital heart disease and the Liver

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A useful review on this topic: Hepatology 2012; 56: 1160-69.

As a result of the successes of surgery for congenital heart disease (CHD), the majority of patients (~85%) with complex CHD survive into adulthood.  Hepatic complications are common in these patients either from the primary cardiac defect, from the surgical procedure, from transfusion or from medications.

Several liver diseases also have congenital heart disease manifestations include the following:

  • Alagille syndrome: 25% with CHD including peripheral pulmonic stenosis and tetralogy of Fallot
  • Abernethy malformation: ASD, VSD, and PDA
  • Biliary atresia splenic malformation syndrome: numerous forms of CHD
  • Mitochondrial fatty acid oxidation disorders: cardiomyopathy

CHD defects associated with hepatic dysfunction:

  • Right-sided failure: single ventricle physiology after Fontan, d-Transposition, Eisenmenger syndrome, Ebstein’s anomaly, tetralogy of Fallot with pulmonary regurgitation.  These disorders lead to passive venous congestion of liver with hepatic zone 3 sinusoidal dilation and sometimes zone 3 necrosis due to ischemia.  Biochemically, a cholestasis pattern predominates.
  • Left-sided failure: left ventricular outflow obstruction/coarctation of aorta, VSD, repaired complete atrioventricular septal defect.  This is associated with hypoperfusion and can lead to ischemia with increased transaminases as well as fibrosis.

Specific issues reviewed include the following:

  • Acute cardiac dysfunction
  • Cardiac dysfunction after Fontan
  • Complications of portal hypertension
  • Imaging (there have been reports of HCC following Fontan)
  • Transplantation: isolated cardiac, isolated liver transplantation, combined heart-liver transplantation

Related blog entry:

Fontan and PLE | gutsandgrowth

Looking ‘Sily’ taking this herb?

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Taking milk thistle (silymarin) does not seem to improve disease status or symptoms with chronic hepatitis C (JAMA 2012; 308: 274-82).

This multicenter, randomized, double-blind, placebo-controlled study examined 154 patients with chronic hepatitis C (HCV).  Mean age was 54 years (71% male).  The study required participants to have an ALT ≥ 65 U/L and all patients had been previously unsuccessfully treated with interferon-based therapy.

Silymarin (Silybum marianum) is an extract of milk thistle.  In the HALT-C trial, 33% of patients with chronic HCV and cirrhosis reported current or past use of silymarin.  It has been shown to have anti-inflammatory and immunomodulator properties via inhibition of NG-κB; in addition, it may have direct effects on HCV replication.

Of the 154 patients, 52 received placebo, 50 received 420-mg silymarin dose, and 52 received 700-mg dose. The trial name was ‘Silymarin in NASH and C Hepatitis’ or SyNCH.  All patients were instructed to take medication three times a day. Only 2 patients in each group (~4%) met the primary outcome of an ALT ≤ 45 U/L.  In addition, HCV RNA levels remained unchanged and were similar between placebo-treated patients and silymarin-treated patients.

In addition, there were no significant changes in physical or mental health components of quality-of-life scores: CES-D (Center for Epidemiologic Studies-Depression), CLDQ (Chronic Liver Disease Questionnaire), and SF-36 (Short-Form 36).

Adverse effects were similar, though silymarin-treated patients had increased GI adverse effects,12% vs 5% among placebo-treated patients.   Though, the study was not powered to detect significant differences with respect to adverse effects.

The major limitation of the study was the patient selection; that is, patients not responsive to interferon may not be representative of all patients with chronic HCV.  While newer HCV therapies have become much more effective, due to their expense, effective less-costly therapies would be helpful.

Unfortunately, milk thistle/silymarin is not likely therapeutic for HCV and thus not cost-effective either.

Related blog entries:

Can NALFD be improved with bile acid sequestration?

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Probably not (Hepatology 2012; 56: 922-32).

Because bile acid sequestrants like colesevelam (& cholestyramine) lower plasma low density lipoprotein (LDL) levels and can improve glycemic control, a recent study tested the hypothesis that this would result in improvement in patients with biopsy-proven nonalcoholic steatohepatitis (NASH).

Methods: 50 patients were randomly assigned to either colesevelam 3.75 g/d or placebo for 24 weeks.  All patients had a liver biopsy within 6 months as a baseline study.  The primary outcome was liver fat as measured by a MRI technique (proton-density fat-fraction or PDFF) and by MR spectroscopy. At the start and conclusion of the study patients had biochemical assays, MRI-PDFF & MR spectroscopy; also, patients had a liver biopsy at completion of study.

Results: The colesevelam group had increased fat at the conclusion of the study period by a mean difference of 5.6% with PDFF and 4.9% with MR spectroscopy, both compared with placebo group.  In addition, liver biopsy did not detect any effect of treatment.  Looking at the biochemical indices, there was also a trend of increased transaminases in the treatment group compared to the control group (Table 3 in study).

Conclusions: The authors indicate that the increased fat may be due to a compensatory increase in bile acid synthesis.  Also, as the changes in fat were only detected on MRI, future NASH studies may benefit from this technique as well.

Related blog entries:

NAFLD Guidelines 2012 | gutsandgrowth

Pediatric NAFLD Position Paper | gutsandgrowth

Vision and persistence in developing liver transplantation

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A concise perspective article examines the history and challenges of developing liver transplantation into an accepted treatment for end-stage liver disease (NEJM 2012; 367: 1483-86).

Key points:

  • Thomas Starzl 1st attempted liver transplant in 1963.  The 3-year-old boy with biliary atresia did not survive the operation; the next 5 attempts were failures as well with the longest survivor lasting only 23 days.  A moratorium of nearly 4 years was placed after these initial failures.
  • Improvements in immunosuppression were a key advance, including antilymphocyte serum in 1966.  During the 1970s, 70% of liver-allograft recipients died shortly after surgery.
  • Brain death concept, accepted in 1968, allowed for better donor organs (less ischemia)
  • Key immunosuppression advance was in 1979 when Roy Calne (Cambridge) reported the use of cyclosporin for organ transplantation.  Between 1980-81, 70% (n=40) of Starzl’s patients survived more than one year.
  • In 1983, National Institutes of Health at a consensus conference concluded that liver transplantation should be considered a ‘clinically applicable, lifesaving procedure.’
  • Other improvements, such as better organ procurement protocols and preservation along with further improvements in immunosuppression have helped improve 1-year and 5-year survival rates to climb, >85% and >70% respectively in 2010.
  • In 2010, 6291 patients underwent liver transplantation.
  • Remaining challenges include inadequate organ supply, recurrent primary hepatic disease (eg. hepatitis C), adverse drug effects, and post-transplantation complications.

The persistence and vision of Starzl and Calne has been recognized with the Lasker-Debakey Award (Lasker-DeBakey Clinical Medical Research Award – Wikipedia, the …).

How strong is the case for HCC screening?

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Not that strong.  The AASLD guidelines for hepatocellular carcinoma (HCC) have faced additional scrutiny and an editorial reviews the basis for HCC screening recommendations (Hepatology  2012; 56: 793-96).

According to the authors, there have been two randomized controlled trials of HCC screening in China.  One that did not demonstrate benefits of HCC screening relied on resection as the treatment for early-stage HCC.  However, a large proportion of those with screen-detected HCC did not undergo resection.

The second trial demonstrated benefit but had several issues.  First, the statistical analysis has been criticized as faulty due to the cluster randomization method while analyzing with an individual patient basis method.  In addition, most North American cases of HCC are related to HCV rather than HBV; thus, the results may not be applicable.

The editorial counters that there are additional lines of evidence that HCC screening is effective for HCV and that an adequate RCT in this country will never be feasible.  Specifically, they suggest that an adequate study would need 10,000 subjects.  This would be further complicated by informed consent; an Australian study has shown that 90% of patients would refuse randomization and prefer to undergo screening.

The editorial points out that advancement in treatments have lowered the likelihood of morbidity in patients identified through screening as well.

As part of their conclusion, the authors quote Sir Austen Bradford Hill who conducted the first RCT in humans: All scientific work is incomplete…liable to be upset by advancing knowledge.  That does not confer upon us a freedom to ignore the knowledge we already have, or to postpone the action it appears to demand at a given time.”

Related blog entry:

Looking for trouble | gutsandgrowth

Additional references: