Category Archives: Hepatology

Ultrasound Unreliable to Exclude Fatty Liver

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More information on the sensitivity of ultrasonography for detecting fatty liver is available in the setting of living-related liver transplantation (Transplantation 2013; 95: DOI: 10.1097/TP.0b013e31828d1588).

In this study the authors retrospectively examined the degree of steatosis from 492 living liver donors who had normal ultrasounds and normal aminotransferase levels. The median age of the donors was 30.1 year and the median BMI was 22.4 kg/meter-squared.

Background: According to the authors, if liver histology shows severe macrosteatosis (>60%), transplantation is canceled.  Furthermore, in cases of moderate macrosteatosis (30-59%), the risks/benefits need to be considered on an individual basis due to increased risk of mortality; Spitzer et al (reference below) demonstrated that macrovesicular steatosis >30% was an independent predictor of reduced 1-year graft survival.  In addition, a previous report has indicated that both macrosteatosis and microsteatosis had similar impacts on postoperative  liver function.

Results:

  • 3 (0.6%) had severe total steatosis, moderate or greater steatosis was diagnosed in 4 (0.8%) for macrosteatosis, in 26 (5.3%) for microsteatosis, and 56 (11.4%) for total steatosis.
  • There were two identified risk factors BMI >23 kg/meter-squared and triglycerides >88 mg/dL.  Individuals with both risk factors had a 28.6% prevalence of moderate or greater degree of total steatosis compared with 6.6% with no risk factors.  In these individuals, a liver biopsy may be worthwhile.

Why this study matters for the non-transplant physician:  This study provides additional data that ultrasonography is not adequate to exclude significant degrees of fatty liver.

Study limitations included the retrospective analysis which relied on medical record accuracy, degree of steatosis was not based on a single pathologist, ultrasonography was not based on not based on a single radiologist, both BMI and triglycerides may vary based on age, gender, ethnicity and other factors.

Related blog entries:

Related references:

  • -Spitzer AL et al. Liver Transpl 2010; 16: 874-84.
  • -Liver Transpl 2013; 19: 437-49. Difficulty with precisely determining steatosis
  • -Hepatology 2011; 54: 1082.  U/S w ~85% sensitivity in detecting fatty liver.
  • -Gastroenterol 2008; 135: 1961.  Liver biopsy (in pediatrics) still needed as surrogates not accurate for correlating degree of fibrosis/injury.
  • -J Pediatr 2009; 155: 469.  Review.  No evidence-based guidelines for treating in pediatrics –main Rx wt loss/exercise.  Consider obtaining ultrasound.

Hepatitis C Virus Sexual Transmission and Monogamy

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Numerous sources state that there is a low risk of transmitting Hepatitis C virus (HCV) among monogamous heterosexual couples.  More information on this subject has been published (Hepatology 2013; 57: 881-89).

In this study, 500 couples were studied; all were long-term heterosexual partners and all were HIV-negative.  The index partner was anti-HCV positive with a median age of 49 years and had a median of 15 years with their partner.  Condom use was infrequent among the study participants.

Key finding: HCV prevalence among partners was 4% (n=20) and ~2% (n=9) had concordant genotype/serotype.  The maximum prevalence of HCV transmission among these sexual partners was 1.2%.  Based on 8,377 person-years of follow-up, the maximum incidence rate of HCV transmission was reported as 0.07% per year or approximately one per 190,000 sexual contacts.

Some of the interesting aspects of the study included details of sexual activity and discussion of factors that may increase HCV transmission.  With regard to sexual activity, 30.4% of the couples reported prior anal intercourse and more than 90% reported oral sex (by both partners); however, both of these activities were reported as infrequent: typically 0 per month for anal intercourse and 3 contacts per month for oral sex.  With regard to HCV transmission, the authors did not identify any risk factors in the current study but did note that this may be influenced by viral titer, integrity of mucosal surfaces, and the presence of other infections.

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Liver toxicity -where to look online

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Increasingly physicians as well as families gather medical information online.  Physicians, like patients, benefit when they know that a website is highly regarded by experts in the field.  This month’s Hepatology (2013: 57: 873-74) provides an introduction to the website LiverTox (www.livertox.nih.gov) (Search Livertox Database).

This website provides comprehensive and “evidence-based information on drug, dietary supplement, and herbal-induced liver injury that is freely accessible to physicians, researchers, and the public.”  The website includes about 650 different medications, supplements, and herbals; more than 12,000 annotated references are available.  In addition, the website allows clinicians to submit a case report as well as allow submission to the FDA Adverse Event Reporting System (AERS).

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More options for Hepatitis C

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As noted in numerous blog entries (see below), there has been increasing availability of new and more effective treatments for Hepatitis C virus (HCV).  Two more drugs have promising results:

  • NEJM 2013; 368: 34-44
  • NEJM 2013; 368; 45-53

The first study provides encouragement with regard to sofosbuvir (previously known as GS-7977) which is a direct-acting nucleotide polymerase inhibitor targeting the NS5B polymerase.

In this open-label study, there were eight groups of patients.  Of 40 previously untreated patients (genotype 2 or 3), all patients received sofosbuvir (400 mg daily) for 12 weeks.  All 10 who received the study drug with ribavirin (& without interferon) and all 30 who received the study drug with ribavirin and peginterferon had a sustained virologic response (SVR) at 24 weeks.  Among patients with sofosbuvir monotherapy, 6 of 10 had a SVR.  Among HCV genotype 1 patients, 21 of 25 (84%) previously untreated patients had a SVR. The most common adverse effects were headache, fatigue, insomnia, rash and anemia.

The second study also was a phase 2a, open-label study for HCV genotype 1 non-cirrhotic patients using ABT-333 and ribavirin.  ABT-333 is a nonnucleoside NS5B polymerase inhibitor.  Results: 17 of 19 (89%) patients in group 1 (Rx with ABT-333, ribavrin, ABT-450, and ritonavir), 11 of 14 (79%) patients in group 2 (Rx with same drugs at lower doses of latter two drugs) had extended rapid virologic response.  SVR was achieved in 95% and 93% respectively.  Groups 1 and 2 were previously untreated.  Group 3 were patients who had either a null or partial response to previous treatment achieved a 47% SVR.  The most common adverse effects were abnormalities in liver function tests, headache, fatigue, insomnia, pruritus, nausea and rash.

Bottom-line:

These preliminary results suggest that Sofosbuvir is effective in all genotypes and may allow a short duration all-oral regimen.  ABT-333 similarly is effective in an all oral regimen in genotype 1 patients.

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Can Hepatitis C really be cured?

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While many have equated a sustained virologic response (SVR) as a cure for hepatitis C virus (HCV), there have been concerns about “occult” hepatitis C.  A new study indicates that in the vast majority of patients with an SVR, there is “no evidence of ongoing HCV replication…and no evidence that HCV replicates in PBMCs of chronically infected patients” (Hepatology 2013; 57: 483-91, editorial 438-40).

There has been no disagreement that an SVR is associated with improved liver histology, improved clinical symptoms, often a reversal of fibrosis, and lower risk of hepatocellular carcinoma.  However, the study and the accompanying editorial summarize the disparity in studies about the potential for occult HCV and how the virus has been identified in the peripheral blood mononuclear cells (PBMCs) and livers of patients who have had an SVR.

The study examined 67 chronic HCV carriers and examined the liver and other tissues of 2 spontaneously recovered chimpanzees.

Key findings:

  • The authors confirm that HCV RNA can be detected in PBMCs in chronic HCV carriers, but only as nonreplicating virus; therefore, it is probably not harmful to the host or to others.
  • Healthy controls had HCV passively adsorbed to PBMCs in vitro becoming indistinguishable from the HCV RNA in PBMCs of chronic HCV carriers
  • HCV RNA could not be detected in the PBMCs of 59 presumed recovered subjects using a highly sensitive nested PCR assay (measure down to 10 IU)
  • In total, this study and others support the likelihood of absolute HCV clearance in most patients with either spontaneous or treatment-induced recovery

Editorialist recommendation: “it seems appropriate to perform virology and biochemical screening annually…particularly if…there was histologic evidence of fibrosis or cirrhosis”

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Gut microbiome and endogenous alcohol

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At first glance, it sounds like an ambitious project -develop a gut microbiome that produces alcohol.  It could obviate the need for “Duff” beer (Duff Beer – Wikipedia, the free encyclopedia).  Yet, a recent article has found that an altered microbiome with increased endogenous alcohol already exists and it is associated with nonalcoholic steatohepatitis (NASH) (Hepatology 2013; 57: 601-609).

In this study, the authors examined three pediatric populations: a healthy control group (n=16), obese group (n=25), and NASH group (n=22).  All NASH patients had undergone liver biopsy and met Kleiner’s criteria; in contrast, the obese group had normal LFTs.

Key study findings:

1. The microbiome from the obese and NASH patients were similar but had some striking differences compared with the control group patients (pie chart –Figure 2):

  • Bacteroidetes (including Bacteroides): 28.65% in healthy controls, 50.28% in obese, and 49.11% in NASH
  • Firmicutes (including Blautia and Faecalibacterium): 66.78% in healthy controls, 42.62% in obese, and 42.39% in NASH
  • Proteobacteria (including Escherichia): 0.87% in healthy controls, 3.13% in obese, and 6.03% in NASH

2. Elevated serum ethanol concentrations only in NASH population: ~26 μM in both control and obese groups compared with ~35 μM in NASH patients.

Under normal conditions, endogenous alcohol is produced in the human body and the intestinal microflora are the major source.  This gut-produced alcohol is quickly metabolized by the liver.  Due to similar histology between NASH patients and patients with alcoholic liver disease, it has been hypothesized that NASH patients may have elevated blood alcohol.  This study adds further evidence to this hypothesis and provides a potential mechanism; namely, increased bacteria like Escherichia and Bacteroides can increase endogenously-produced alcohol.

Will efforts to revert the microbiome to normal have therapeutic effects on NASH?  This important question will need to be addressed given the growing problem of fatty liver disease.

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Practice guidelines and 93 OLTx recommendations

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While checklists have a role (Checklists for Crisis and Daily Care | gutsandgrowth), most will not be workable if each has 93 recommendations like the 2012 AASLD Adult Liver Transplant Practice Guidelines (Liver Transplantation 2013; 19: 3-26).

While the guidelines are comprehensive including topics like vascular thrombosis, immunosuppression, late rejection, bone health, kidney diseases, metabolic syndrome, reproductive health, and infectious disease, they are not easily organized.  Some recommendations include the following:

  1. “the frequency of monitoring with liver tests should be individualized by the transplant center (grade 1, level a)”
  2. “depending on the pattern of liver tests, magnetic resonance imaging, computed tomography, ERCP, and ultrasound may be appropriate (grade 1, level a)”
  3. “frequent handwashing reduces the risk of infection…(grade 1, level a)”
  4. “shoes, socks, long-sleeve shirts and long pants should be worn for activities that will involve soil exposure..(grade 1, level a)”
  5. Patients “with PSC and inflammatory bowel disease…should undergo an annual screening colonoscopy ..(grade 1, level b)”
  6. “the ideal immunosuppression for pregnancy is tacrolimus monotherapy”

Thus, the recommendations are sometimes almost worthless like #1-3, sometimes difficult to implement like #4, and sometimes specific like #5-6.

Bottom-line:

While not useful as a practical checklist for routine care, this guideline offers useful information on a broad range of problems for transplant recipients.

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.

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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.

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