Category Archives: Hepatology

Thrombophilia and Portal Vein Thrombosis

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Most cases of portal vein thrombosis (PVT) remain without apparent explanation (JPGN 2012; 55: 599-604).

In this study from Brazil, 32 children with portal vein clots (1990-2011) were reviewed in this cross-sectional study.  The median age at diagnosis was 2.4 years.  Hereditary or acquired thrombophilia was detected in 34% and 9 of these patients had identified risk factors.

The most common thrombophilia factor was the presence of heterozygous state for methylenetetrahydrofolate reductase (MTHFR) C677T which was present in 11 patients.   2 of these patients had a cofactor, including G20210A prothrombin gene, and factor V Leiden.

Risk factors included umbilical catheterization in 13 patients (40.6%).

18 (56%) had no risk factors. 

Related blog entry:

VTE with IBD | gutsandgrowth

Additional references:

  • -Hepatology 2009; 39: 1729.  AASLD practice guidelines on vascular disorders. Recs mesoRex shunt for PVT.
  • -JPGN 2008; 47: 630. n=108. Infrequent thrombophilia d/o with PVT. Banding/sclero -effective.
  • -J Pediatr 2006; 148: 735. PVT more common than previously thought; umbilical vein catheter, esp if misplaced, is risk factor.
  • -NEJM 2011; 365: 147. Review. In cirrhosis pts, platelet count as low as 60K usually sufficient to preserve thrombin generation equivalent to lower limit of normal range in healthy subjects. PVT occurs in 8-25% of pts listed for OLTs. Thus, many procoagulant factors as well as potential propensity for bleeding.
  • -J Pediatr 2003; 142: 197. Rex procedure corrects clotting abnormalities.
  • -J Pediatr 2005; 146: 568. Portal vein -cavernous transformation –associated with cholestasis.
  • -J Pediatr 2000; 136: 805. 49% of children with PV clot had bleeding by 16 yrs & 76% by 24 yrs. (n=44).
  • -Gastroenterol 2001; 120: A-49, #256. Attention span deficits can be corrected c REX.
  • -Hepatology 2000; 31: 345-348 & 587-591. Hyperhomocysteine mutation frequent when PVT assoc c cirrhosis. Etiologic factors. 87% c thrombophilic d/o.
  • -Gastroenterol 2001; 120: 490-497 & 579. Anticoagulation helpful.
  • -J Peds 2006; 149: 275. Reference values.
  • -NEJM 2005; 352: 1791. Thrombosis of cerebral veins & sinuses (review); includes assoc c IBD.  Specific thrombophilia disorders: Antithrombin deficiency, protein S and C deficiencies,Factor V Leiden mutation, (the A for G 20210) prothrombin gene mutation, lupus anticoagulant, antiphospholipid antibodies, factor XI, and MTHFR-hyperhomocysteinemia (thermolabile variant of methylenetetrahydrofolate reductase- C677T MTHFR-). The later was paricularly interesting in view of the recent report of hyperhomocysteinemia in patients with inflammatory bowel disease (Thromb Haemost 1998,80;542-5)

Learning a new language for HCV

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There is bad news for those of us finally comfortable with the terms and abbreviations of the hepatitis C virus lexicon, like rapid virological response (RVR) and complete early virological response (cEVR).  A new consensus is emerging that more precise nomenclature is needed in this era of direct-acting antivirals (DAA) (Hepatology 2012; 56: 2398-2403).

The problem is that with the use of DAA, drugs that use a 4-week lead-in have their RVR checked at 8 weeks rather than 4 weeks.  Similar problems are present with the other terminology in current use.

RVR should be reported as W4U-tnd.  W4 indicates week 4, U indicates viremia unquantifiable, tnd indicates whether target HCV RNA was not detected (td indicates detected). If there is a lead-in, then LI-w/d-W8U-tnd.

Other terms:

  • vRVR or very rapid virological response is now W2U-tnd
  • eRVR or extended RVR refers to undetectable HCV RNA at week 4 and 12 and is now W4-12U-tnd
  • cEVR refers to undetectable HCV RNA at 12 weeks is now W12U-tnd
  • pEVR or partial EVR indicates at least 2 log10 decrease in HCV RNA after 12 weeks of treatment.  New lingo: W12[-2]
  • SVR or sustained virological response is now SVR12-tnd (if 12 weeks after Rx) and SVR24-tnd (if undetectable HCV RNA 24 weeks after Rx)
  • LLOQ indicates the  lower limit of quantitation.  A value <LLOQ is not necessarily “undetectable.”

You may need the hepatology ‘rosetta’ stone session before your next meeting with your liver expert.

Related blog entries:

HBV: translating advances from adults to pediatrics

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Given the increased difficulties of conducting research in the pediatric population, it can take a long time for pediatric patients to benefit from the research advances demonstrated in adults.  Fortunately, with hepatitis B virus (HBV) the lag time has not been excessive.  A specific example has been a recent study demonstrating the effectiveness of tenofovir in the pediatric population (Hepatology 2012; 56: 2018-26).

In this double-blind, placebo-controlled study,  adolescents with chronic HBV were randomized into tenofovir 300 mg (n=52) or placebo (n=54) once daily for 72 weeks.  101 patients completed the 72 weeks of treatment.  In this population, 85% had received prior HBV therapy and 91% were HBeAg-positive at baseline.  Patients included in the study had to have ALT >2 x ULN or history of this w/in 24 months along with HBV DNA>10 to the 5th copies/mL.  The inclusion criteria required a weight of >35 kg.

Findings:

  • Virologic response (HBV DNA <400 copies/mL): 89% in tenofovir group and 0% in placebo group
  • No resistance noted through 72 weeks.  All cases of virologic breakthrough were associated with non-adherence but no genotypic or phenotypic resistance.
  • Normalization of ALT: among patients with baseline elevation, normalization occurred in 74% of tenofovir group compared with 31% of placebo group
  • Serologic response: 21% of tenofovir group and 15% of placebo group experienced loss of HBeAg by week 72
  • Adverse effects were more frequently noted in placebo group.  No patients met the safety endpoint of a 6% decrease in spine bone mineral density

Since suppression of HBV DNA is a limited surrogate endpoint for the development of long-term sequelae much longer followup is needed to determine the impact of this nucleotide analogue.  In adults, this agent has been associated with reversal of cirrhosis.

Across the globe, 350 million people live with chronic HBV infection and 600,000 die each year due to HBV infection.  About 25% of children with HBV develop cirrhosis or cancer of liver later in life.  Given the magnitude of the problem, the most promising approach remains prevention with vaccination.  Treatment to prevent complications in those already infected is likely to be offered to a tiny fraction of those who might benefit.

Related blog entries:

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: