Understanding Cholestatic Pruritus

Posted on August 4, 2014 by gutsandgrowth

A recent review (Hepatology 2014; 60: 399-407) sorts out “facts and fiction” with regard to pruritus in cholestasis.

The authors note that for more than 2000 years there has been a search for the potential pruritogen in cholestasis, “when Aretaeus the Cappadocian (2nd century B.C.) stated that ‘pruritus in jaundiced patients is caused by prickly bilious particles.'”

Key points of review:

Pruritus affects a large number of hepatobiliary diseases

Hepatocellular cholestasis: intrahepatic cholestasis of pregnancy (ICP), benign recurrent intrahepatic cholestasis (BRIC), progressive familial intrahepatic cholestasis (PFIC1, PFIC2), Hepatitis C
Biliary-liver diseases: primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), PFIC3, Alagille, Drug-induced diseases
Obstructive cholestasis: gallstones, IgG4-associated cholangitis, biliary atresia, and other causes

Most recently lysophosphatidic acid LPA) and autotaxin (ATX) have been shown to be important pruritogen candidates in cholestasis

“ATX is the main source of circulating LPA levels…In cholestasis, serum ATX activity, but not other putative markers of itch such as serum bile salt levels or serum μ-opiod activity, were correlated with itch intensity.”
“Rifampicin was found to reduce ATX expression at the transcriptional level.” This may explain rifampicin’s efficacy for pruritus in cholestasis.
“When the enterohepatic circulation is interrupted by nasobiliary drainage, circulating levels of ATX rapidly dropped concomitant with relief of pruritus.” So, while ATX is not secreted into bile, other substances in bile, like steroid hormones, like play a role in the induction of ATX.

Current therapeutic recommendations (dosing recommendations provided by authors in Table 3)

1st line: Cholestyramine (except in ICP in which ursodeoxycholic acid is considered 1st line)
2nd line: Rifampicin
3rd line: naltrexone
4th line: sertraline
Experimental: ondansetron, phenobarbitol, propranolol, lidocaine, dronabinol, butorphanol, phototherapy, nasobiliary drainage, plasmapharesis (and similar treatments), biliary diversion
Liver transplantation

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Using Preoperative Aspirin to Prevent Postoperative Problems –Negative Study

Posted on August 3, 2014 by gutsandgrowth

A recent study has looked at whether giving aspirin prior to surgery can help those who take aspirin and also those who do not (NEJM 2014; 1494-503). This trial called POISE-2 (Perioperative Ischemic Evaluation 2) was undertaken to determine if low-dose aspirin, as compared to placebo, would affect 30-day risk of death or nonfatal myocardial infarction.

The relevance of this study relates to aspirin’s known potential for preventing venous thromboembolism and the fact that “one-third of patients undergoing noncardiac surgery who are at risk for major vascular complications receive perioperative aspirin.”

The study enrolled 10,010 patients and employed a 2-by-2 trial design to account for whether they had been taking aspirin. The study took place between 2010-2013 at 135 hospitals and 23 countries. Mean age was 68 years in both groups.

Results:

The rate of death was similar in both groups: 7.0% for aspirin and 7.1% for placebo (hazard ratio 0.99)
Major bleeding was more common with aspirin than placebo: 4.6% vs. 3.8% (P=0.04).

Bottomline: Perioperative aspirin had no significant beneficial effect.

Related study: NEJM 2014; 370: 1504-13. Conclusion: “Administration of low-dose clonidien in patients undergoing noncardiac surgery did not reduce the rate of” death or nonfatal myocardial infarction. Patients who received clonidine had more frequent hypotension and nonfatal cardiac arrest.

Walking with a “Z” or an “X”

Posted on August 2, 2014 by gutsandgrowth

In a number of media outlets, there has been a push for a highly successful (and under appreciated) treatment: walking.

Advantages:

No/Low cost
Easy
Often fun
Excellent side effect profile

Here’s a link (Every Body Walk!) and here’s an excerpt:

Researchers have discovered a “wonder drug” for many of today’s most common medical problems, says Dr. Bob Sallis, a family practitioner at a Kaiser Permanente clinic in Fontana, California. It’s been proven to help treat or prevent diabetes, depression, breast and colon cancer, high blood pressure, cardiovascular disease, obesity, anxiety and osteoporosis, Sallis told leaders at the 2013 Walking Summit in Washington, D.C.

“The drug is called walking,” Sallis announced. “Its generic name is physical activity.”

Recommended dosage is 30 minutes a day, five days a week, but children should double that to 60 minutes a day, seven days a week. Side effects may include weight loss, improved mood, improved sleep and bowel habits, stronger muscles and bones as well as looking and feeling better.

Comment: If only “walking” was marketed better. Physicians know that successful treatments need to have an “x” or a “z” or both to really do well (“X and Z in favor”).

Not Much Data with Allopurinol

Posted on August 1, 2014 by gutsandgrowth

The authors of a recent case report (JPGN 2014; 59: 22-24) note that there has been “only 1 study on the pediatric use of allopurinol in inflammatory bowel disease.” A previous post on this blog has reviewed the use of allopurinol for IBD and provided several references –mainly from use in adults (Data on Allopurinol | gutsandgrowth).

This current study reports on three cases. In all three cases the combination of allopurinol with low-dose 6-mercaptopurine resulted in clinical remission, including one patient which was poorly responsive to infliximab. In all three cases, frequent thiopurine metabolites were obtained to help guide dosing. Prior to allopurinol, all 3 patients had a 6-MMP/6-TG ratio >20; with use of allopurinol there was a decrease in this ratio.

Among these patients, one developed mild leukopenia which resolved with medication adjustment.

Bottomline: Allopurinol can be effective in optimizing thiopurine treatment, but need to be administered carefully. More studies on its use are needed.

Skinnier TVs and Heavier Kids

Posted on July 31, 2014 by gutsandgrowth

A recent study showed an association between having a TV in the bedroom with increased weight gain (JAMA Pediatrics 2014; 168: 427-34). Here’s a link: Bedroom TV and obesity study. My emphasis in bold:

Design: “We conducted a random-digit prospective telephone survey that captured children and adolescents from across the United States. Participants included 6522 boys and girls aged 10 to 14 years at baseline who were surveyed via telephone about media risk factors for obesity. Weighted regressions assessed adiposity at 2- and 4-year follow-up, controlling for television and movie viewing, video-game playing, parenting, age, sex, race or ethnicity, household income, and parental educational level.”

Results: “Distributions for age, sex, race or ethnicity, and socioeconomic status were similar to census estimates for the US population. Sample weighting methods accounted for higher dropout rates among ethnic minorities and those with lower socioeconomic status. Bedroom televisions were reported by 59.1% of participants at baseline, with boys, ethnic minorities, and those of lower socioeconomic status having significantly higher rates. In multivariate analyses, having a bedroom television was associated with an excess BMI of 0.57 (95% CI, 0.31-0.82) and 0.75 (0.38-1.12) at years 2 and 4, respectively, and a BMI gain of 0.24 (0.02-0.45) from years 2 to 4.”

Conclusion: “Having a bedroom television is associated with weight gain beyond the effect of television viewing time. This association could be the result of uncaptured effects of television viewing or of disrupted sleep patterns. With the high prevalence of bedroom televisions, the effect attributable to this risk factor among US children and adolescents is excess weight of 8.7 million kg/y.”

Comment: While this study targets TV, “screen time” has now expanded to cell phones, tablets, and computers. All of these may be detrimental to physical well-being.

Related blog posts:

Epidemic of Aggressive Care vis-a-vis Breast Cancer

Posted on July 30, 2014 by gutsandgrowth

In many areas of medicine, the need for increased certainty of cure and diagnostic certainty leads to other problems; sometimes, “the perfect is the enemy of the good.” While this happens in pediatric gastroenterology, the frequency is probably greatest in oncology. A recent terrific article in the NY Times by Peggy Orenstein highlights an epidemic of contralateral prophylactic mastectomy (CPM) in the care of patients with breast cancer.

Here are a couple of points and the link –Wrong Approach to Breast Cancer:

According to a study published in the Journal of Clinical Oncology in 2009, among those with ductal carcinoma in situ — a non-life-threatening, “stage 0” cancer — the rates of mastectomy with C.P.M. jumped 188 percent between 1998 and 2005. Among those with early-stage invasive disease, the rates went up 150 percent between 1998 and 2003. Most of these women did not carry a genetic mutation, like the actress Angelina Jolie, that predisposes them to the disease.
Overestimation of their actual chances of contracting a second cancer. In a 2013 study conducted by the Dana-Farber Cancer Institute in Boston, for instance, women under 40 with no increased genetic risk and disease in one breast believed that within five years, 10 out of 100 of them would develop it in the other; the actual risk is about 2 to 4 percent.
Underestimated the potential complications and side effects of C.P.M. Breasts don’t just screw off, like jar lids: Infections can occur, implants can break through the skin or rupture, tissue relocated from elsewhere in the body can fail. Even if all goes well, a reconstructed breast has little sensation. Mine looks swell, and is a remarkably close match to its natural counterpart, but from the inside it feels pretty much like a glued-on tennis ball.
The most comprehensive study yet, published earlier this month in the Journal of the National Cancer Institute, showed virtually no survival benefit from the procedure — less than 1 percent over 20 years.
How can that be? Well, first of all, it is extremely rare for a tumor on one side to spread to the other. Cancer doesn’t just leap from breast to breast.

Naloxegol for Opioid-Induced Constipation

Posted on July 29, 2014 by gutsandgrowth

Opioid narcotics are ubiquitous therapeutic agents for acute and chronic pain. In the United States, more than 240 million opioid prescriptions are dispensed per year. One of the most common sided effects is constipation. The mechanism of this side effect is the binding of opioid agonists to μ-opioid receptors located in the enteric nervous system.

The recognition of this mechanism has allowed the development of μ-opioid receptor antagonists. A recent study has shown that Naloxegol helps treat constipation related to opioids in patients with noncancer pain (NEJM 2014; 370: 2387-96). Naloxegol is a pegylated derivative of the μ-opioid receptor antagonist naloxone. Pegylation limits the ability of naloxegol to cross the blood-brain barrier; hence, the central pain effects of narcotics are not blocked whereas the effects on the enteric nervous system are limited.

This study reported the results of two phase 3, double-blind studies with a combined 1352 participants. Response to treatment was defined as having ≥3 spontaneous BMs/week and an increase in baseline of ≥1 spontaneous BM/week for ≥9 of 12 week study period and for ≥3 of the final 4 weeks.

Key results:

Response to Naloxegol at 25 mg dosing: 44.4% in first study and 39.7% in second study (compared with 29% of placebo treated patients in both studies).
Most adverse effects were mild to moderate and included increased abdominal pain, diarrhea, nausea, and flatulence. Major cardiovascular events were rare and not increased compared to placebo.

Related blog posts:

You Still Need the Data

Posted on July 28, 2014 by gutsandgrowth

A recent study (J Pediatr 2014; 165: 23-9) confirmed the obvious: “early empiric antibiotic use in preterm infants is associated with lower bacterial diversity.” That being said, you still need the data and the specific changes are of importance.

This study examined the stools from 74 preterm infants (≤32 weeks gestational age) and determined how the microbiota changed in relation to no antibiotics (18% of cohort), brief antibiotics (1-4 days) (64% of cohort), or ‘intensive’ antibiotics (5-7 days) (18% of cohort). Empiric antibiotics consisted of ampicillin and gentamicin. Stools were analyzed with the 16s ribosomal DNA community profiling.

The key findings are graphically shown in Figure 1 with pie charts showing the relative abundance of 10 bacterial genera at week 1, week 2, and week 3 in each of the three groups.

Those who received 5-7 days of antibiotics had the most changes in their microbiota with increased Enterobacter and lower bacterial diversity in the second and third weeks of life.
In those who received no empiric antibiotics there was increasing bacterial diversity noted sequentially. These changes were not seen in either of the antibiotic groups. However, the group with brief antibiotic exposure returned to their baseline diversity by week 3.
Infants receiving early antibiotics experienced more cases of necrotizing enterocolitis, sepsis and death than those who were not exposed to antibiotics (this was not proven to be casually-related).

Take-home message: This study proves that antibiotics change the microbiome in neonates and that neonates exposed to antibiotics may have complications as a result. Better biomarkers (with rapid turn around time) would allow more careful selection of which neonates need empiric antibiotics.

Medical School Student vs. Dr. Oz

Posted on July 27, 2014 by gutsandgrowth

A recent link from Vox (highlight on KT Park’s twitter feed) highlights a medical student’s actions against Dr. Oz’s pseudoscience.

Here’s an excerpt:

Benjamin Mazer is a third-year medical student at the University of Rochester. Last year, after becoming increasingly concerned with the public-health impact of Dr. Mehmet Oz’s sometimes pseudoscience health advice, he decided to ask state and national medical associations to do something about it.

“Dr. Oz has something like 4-million viewers a day,” Mazer told Vox. “The average physician doesn’t see a million patients in their lifetime. That’s why organized medicine should be taking action.”…

We had all of this first-hand experience with patients who really liked his show and trusted him quite a bit. [Dr. Oz] would give advice that was really not great or it had no medical basis. It might sound harmless when you talk about things like herbal pills or supplements. But when the physicians’ advice conflicted with Oz, the patients would believe Oz….

I wrote policy for the Medical Society of the State of New York [where Dr. Oz is licensed] and the American Medical Association asking them to more actively address medical quackery on TV and in the media—specifically Dr. Oz.

Related blog posts:

Understanding Breast Milk Jaundice

Posted on July 26, 2014 by gutsandgrowth

A recent study of 170 Japanese infants with breast milk jaundice (BMJ) demonstrated that 52% had a homozygous mutation: UGT1A1*6 (J Pediatr 2014; 165: 36-41). The study included 55 controls without BMJ.

Defects in UGT1A1 have been associated with a number of hereditary unconjugated hyperbilirubinemias including Crigler-Najjar type 1 in which there is complete deficiency of the enzyme Crigler-Najjar type 2 in which there is limited activity of the enzyme, and Gilbert syndrome in which there is moderate activity of the enzyme (but less than general population).

In this study, none of the control population had the UGT1A1*6 homozygous mutation. The authors note that “the components of breast milk clearly contribute to the onset of neonatal jaundice. Our in vitro investigation showed the inhibitory effect of 5α-pregnane-3α, 20β-diol on UGT1A1 activity.” Thus, this may help explain why cessation of breastfeeding for a short period can improve BMJ.

Take-home message: In this Japanese population, the UGT1A1*6 homozygous mutation is an important reason for BMJ. Yet, for about half of all infants another, yet unidentified mechanism(s), is responsible.