Category Archives: Hepatology

Population-Based Outcomes for Primary Sclerosing Cholangitis

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A study from the Netherlands examined the outcomes for Primary Sclerosing Cholangitis (PSC) (Hepatology 2013; 2045-55). Using four independent hospital databases with 44 hospitals, allowed the investigators to identify 590 PSC patients from a population of almost 8 million. Median followup was 92 months. Mean age at diagnosis was 38.9 years.  A second comparison cohort of 450 patients was identified from three Dutch transplantation centers outside the study area.  134 (30%) of this cohort were present in the population-based cohort.  An IBD comparison group of 722 cases was identified as well from a population of 271,000 patients.

Results:

  • Prevalence: 6 per 100,000.  This is significantly lower than previous estimates.  The authors emphasize the problem with previous epidemiology studies and the need for population-based studies with rigorous case-finding.
  • Survival, estimated at 21.3 years for the entire cohort following diagnosis, was better than previous studies and this may indicate less selection bias than tertiary referral center studies.  It could also reflect diagnosis of milder cases with newer imaging techniques.
  • 402 (68%) of PSC patients were diagnosed with inflammatory bowel disease.
  • 23 (4%) had autoimmune hepatitis overlap.
  • Colorectal cancer was 10-fold increased compared to ulcerative colitis controls and developed at a younger age (39 years compared with 59 years).
  • Cholangiocarcinoma (CCA) was nearly 400-fold increased risk.  The cumulative risk of CCA was estimated at 20% after 30 years following PSC diagnosis.
  • During followup, there were 97 deaths; 73 (75%) were PSC-related.

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Liver fibrosis in determining treatment for Hepatitis B

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A recent editorial reviews current guidelines and makes the point that while patients with advanced fibrosis should receive antiviral treatment, treatment is also recommended for patients with high levels of HBV DNA and active liver disease (Clin Gastroenterol Hepatol 2013; 11: 1500-02).  The related study (Clin Gastroenterol Hepatol 2013; 11: 1493-99) indicated that guidelines do not predict accurately which patients have ≥F2 fibrosis.  The editorial argues that the study’s conclusions are “misguided” because ALT and HBV DNA are not used solely for identifying patients with fibrosis.

Key points:

  • 18-47% of HBV-related HCC occurs in the absence of cirrhosis.
  • Guidelines “agree that treatment should be initiated in non-cirrhotic patients with serum HBV DNA >20,000 IU/mL and alanine aminotransferase (ALT) levels higher than 2 times upper limit of normal (ULN) or histologic evidence of moderate-to-severe inflammation or fibrosis.”
  • For HBeAg-negative patients, AASLD guidelines suggest a lower threshold for HBV DNA (>2000 IU/mL) along with ALT >2 times ULN or ALT 1-2 times ULN with concerning liver biopsy (particularly in age >40 years).
  • “Since treatment does not eradicate the virus…and in many instances [is] lifelong treatment, we agree with Sanai et al that criteria for initiating hepatitis B treatment in guidelines must be carefully weight to avoid unnecessary treatment.”

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It is a Question of Fairness

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One of my professors in medical school frequently described ethical issues in terms of some things being unfair and some things being unfortunate.  A report in this month’s Liver Transplantation (2013: 19: 1330-42; editorial 1287-88) indicates that sometimes an individual does not receive a liver transplant due to an unfair allocation policy.  One potential problem with the current UNOS distribution is the use of exception points.  Because the Model for End-Stage Liver Disease (MELD) score does not work well for all patients, there are both recognized exceptional diagnoses (REDs) (eg. hepatocellular carcinoma) and non-REDs (eg. cholangitis).  The purpose of these exception points is to account for some conditions that may increase the risk of dying on the transplant list in which the MELD score is not an adequate predictor.

In this study of adult liver transplant candidates between 2002-2011, the authors examined non-REDs; among a cohort of 58,641, 7.4% applied for a non-RED.  The number of non-REDs increased over the course of the study.  In addition, approval rates which were <50% in 2002 increased to nearly 75% in 2010. Candidates with approved exceptions were more likely to undergo transplantation (68.3% vs. 53.4%, P <0.001).

There was significant variability among transplant centers with regard to requesting exception points. Centers with higher median MELD score at transplantation were more likely to have candidates with non-RED applications. The net result was that women, African-Americans, Hispanics, and patients with Medicaid insurance were statistically less likely to have an exception application.

In pediatrics, non-RED applications are more common. Thus, the problem of equitable distribution could be even greater among pediatric patients.

Bottomline: While physicians have a duty to their patients, it is vital to make sure that every effort is made to allocate organs in a fair manner.  Since the use of non-RED applications is inconsistent, it suggests that some transplant centers are utilizing this tool inappropriately (?too often, ?too few).  This report indicates that more work is needed to have a fair transplant allocation system.

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Electronic Order Sets Can Improve Care

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It is recognized that checklists can improve medical care as well as help you remember to pick up butter when you go shopping.  So, it is not surprising that a standardized electronic order set can improve patient care.  A recent prospective observational study has shown that implementation of an electronic order set improved the care of 123 patients with cirrhosis who presented with upper gastrointestinal hemorrhage (Clin Gastroenterol Hepatol 2013; 11: 1342-1348).

This study was conducted from 2011 to 2012.

Key findings:

  • Administration of antibiotics increased in patients in whom the order set was used: 100% compared with 89%. A previous Cochrane meta-analysis has noted a mortality risk reduction of nearly 20% in patients who received prophylactic antibiotics in this setting.
  • Order set usage was associated with quicker administration of antibiotics: 3h28min compared with 10h4min.
  • Time for octreotide administration was reduced in patients with the order set: 2h16min vs 6h21min.
  • Mortality was not reduced in this study by using an order set.  In fact, in those who used an order set there were 7 mortalities (out of 61) compared with only 2 mortalities (out of 62) who did not use order sets.

Order set use was at the discretion of the treating physician.  This could have led to selection bias.

Bottomline: Use of a standardized order set improved adherence and timeliness of recommended therapies.

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Wiping out Hepatitis C

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Here’s the view of the NY Times (nyti.ms/1b7nTbl ) about the new therapies for Hepatitis C:

Medicine may be on the brink of an enormous public health achievement: turning the tide against hepatitis C, a silent plague that kills more Americans annually than AIDSand is the leading cause of liver transplants. If the effort succeeds, it will be an unusual conquest of a viral epidemic without using a vaccine.

“There is no doubt we are on the verge of wiping out hepatitis C,” said Dr. Mitchell L. Shiffman, the director of the Bon Secours Liver Institute of Virginia and a consultant to many drug companies.

Over the next three years, starting within the next few weeks, new drugs are expected to come to market that will cure most patients with the virus, in some cases with a once-a-day pill taken for as little as eight weeks, and with only minimal side effects.

That would be a vast improvement over current therapies, which cure about 70 percent of newly treated patients but require six to 12 months of injections that can bring horrible side effects.

The latest data on the experimental drugs is being presented at The Liver Meeting in Washington, which ends Tuesday [11/5/13]

But the new drugs are expected to cost from $60,000 to more than $100,000 for a course of treatment.

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PSC 2013 Review

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A recent review of PSC was published (Gastroenterology 2013; 145: 521-36).  This review is a little more detailed than a previous review noted in this blog less than 6 months ago (Staying current with PSC | gutsandgrowth).

A couple of useful comments from the review:

  • “An increased serum level of alkaline phosphatase is the most common biochemical abnormality detected in patients with PSC.  In some cases, it is the only biochemical alteration observed, such as in patients with intrahepatic involvement.”
  • “Typically, a liver biopsy is not required to diagnose PSC unless small duct PSC is suspected or if there are concerns that a patient also has AIH.”  Cholangiography is the best way to identify PSC.
  • “Patients diagnosed with PSC should undergo colonoscopy… to determine if they have IBD, even when there are no symptoms.”
  • Autoimmune hepatitis-PSC overlap is thought to occur in ≤6% of cases.  AIH-PSC should be suspected if there are biochemical features of AIH (positive serology, increased transaminases), histology suggestive of AIH, or in AIH patients that become refractory to treatment.
  • No controlled trials have identified effective medical treatments.  Studied medications have included corticosteroids, etanercept, tacrolimus, cyclosporine, azathioprine, methotrexate, infliximab, and ursodeoxycholic acid.  The latter may increase disease progression, particularly at higher doses.

Also noted:

Hepatology 2013; 58: 1392-1400. “Primary Sclerosing Cholangitis, Autoimmune Hepatitis, and Overlap in Utah Children: Epidemiology and Natural History”

In this study the authors identified 607 cases of IBD, 29 cases of PSC, 12 cases of ASC (overlap), and 44 cases of AIH.  “Cholangiocarcinoma developed in 2 of the 29 PSC patients (6.9%).  PSC occurred in 9.9% of patients with ulcerative colitis (UC) and 0.6% of patients with Crohn’s disease.”

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and specific medical management interventions should be confirmed by prescribing physician.  Application of the information in a particular situation remains the professional responsibility of the practitioner.

Breakthrough for Fatty Liver Disease?

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Could bile acids play a role in reducing metabolic syndrome and in particular fatty liver disease?  This question is now being studied (Gastroenterology 2013; 145: 574-82).

This recent study examined whether obeticholic acid (OCA) which is a semisynthetic derivative of the human bile acid chenodeoxycholic acid could aid with insulin resistance and ultimately nonalcoholic fatty liver disease (NAFLD).  OCA is an agonist of the farnesoid X receptor which is a nuclear hormone receptor that regulates glucose and lipid metabolism.

The authors performed a phase 2, double-blind, placebo-controlled study to assess the effects of OCA on insulin sensitivity in patients with NAFLD and type 2 diabetes mellitus.  Patients received either placebo (n=23), 25 mg OCA (n=20), or 50 mg OCA (n=21) once daily for 6 weeks.  Using an insulin clamp, insulin sensitivity was measured before and after the study period.  Numerous blood tests were obtained as well.

Results:

  • Insulin sensitivity improved 28% in the 25mg OCA group and 20.1% in the 50 mg OCA group whereas it decreased 5.5% in the placebo group.
  • The OCA groups also had significant reductions in gamma-glutamyltransferase, alanine aminotransferase, and dose-related weight loss.
  • Markers of liver fibrosis decreased in the 25 mg OCA group.
  • Side effects of OCA were minimal.  Constipation was reported in the 50 mg OCA group.

Take-home message: OCA may help patients with NAFLD and a bigger, longer study is in the works (FLINT study: 25 mg OCA for 72 weeks compared with placebo, http://www.clinicaltrials.gov; NCT01265498)

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Do antivirals lower the risk of Hepatocellular Carcinoma in HBV?

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Meaningful endpoints of therapy are often difficult to demonstrate in clinical studies due to the length of followup that may be needed.  For patients infected with hepatitis B virus (HBV), most clinical studies use surrogate biologic, virologic and histologic markers rather than endpoints like hepatocellular carcinoma (HCC) and death.  In addition, long-term randomized trials with untreated controls are difficult to justify given the success of current treatments in improving these surrogate markers.

A recent Japanese study (Hepatology 2013; 58: 98-107 and editorial pg 18) reports data on a large entecavir-treated cohort (n=472) which was matched with a historical control (retrospective control group, n=1143).  The authors used propensity score matching to eliminate any baseline differences.

Findings:

  • Cumulative incidence of HCC rate at 5 years was 3.7% (for entecavir group) and 13.7% (for controls)
  • Using regression analysis and adjusting for known HCC risk factors, patients treated with entecavir had a hazard ratio of 0.37 for developing HCC.
  • Patients with more risk factors for HCC (eg. older, more active disease, cirrhosis) obtained greater benefit from entecavir treatment (shown in Figure 4 in manuscript)
  • The authors also showed that entecavir-treated patients also had less risk of developing HCC than lamivudine-treated patients
  • Entecavir-treated patients had low rates of resistance (0.8%) at 3.2 years of treatment

Take-home message: suppression of viral replication in HBV cirrhosis patients reduces but does not eliminate the risk of HCC.  In noncirrhotic patients, the magnitude of risk reduction is less.  Thus, patients with active disease should be treated.

Causes of Death with Hepatitis B in U.S.

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A recent study followed 6,689 patients with hepatitis B virus (HBV) between 1996-2005 and analyzed causes of death (Hepatology 2013; 58: 21-30, editorial pg 6). This study used a large prospectively-collected database.

The patients were all part of Kaiser Permanente Northern California health plan.  Patients were not eligible if they were coinfected with HIV or HCV.  Causes of death were divided into HBV-related (eg. decompensated cirrhosis [DCC], hepatocellular carcinoma [HCC]) and other causes, including cancer and cardiovascular.

Among this cohort, 68.3% were Asian-Pacific Islander (API) descent, and 11.8% were white (non-hispanic); the remainder were other or unknown descent.  The cohort had a mean age of 41 years.

Findings:

  • Males had higher overall 10-year death rates than females for total deaths (8.9% versus 4.1%) and for HBV-related deaths (4.8% versus 1.2%).
  • 46.7% of all deaths were HBV-related.
  • Death rate rose with increasing age; approximately 40% of deaths after age 40 were HBV-related.
  • Among HBV-related deaths, the death rate from HCC was twice the rate of DCC
  • “We did not find that subjects of API descent origin were at higher risk of death from HBV-related complications.”  This was unexpected because presumably “they are often infected in childhood and therefore have disease of longer duration.”
  • Limitations included absence of data on alcohol, cigarettes and coffee.  In addition, the study period occurred when treatment options for HBV were more limited.

The accompanying editorial notes wide variability in mortality outcome data depending on the study setting.   “Studies in patients with incidentally detected HBV infection, mostly conducted in blood donors in Western countries, tend to portray a benign course…with…their incidence of complications of chronic liver disease, HCC, or liver-related mortality is not significantly higher than that in hepatitis B surface antigen-negative healthy controls.”  In China, the lifetime risk for an infected patient to die from an HBV-related cause “has been estimated to be up to 50% in men and 15% in women.”

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