Monthly Archives: March 2016

What happens with 98,500 IU/day of Vitamin A

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An interesting case report (LA Beste et al. NEJM 2016; 374: 73-8) reviews the presentation of a previously healthy 54 year old with ascites.  He initially indicated that he was taking 100 IU per day of vitamin A (his current dose), but later on directed questioning admitted that he had averaged 98,500 IU/day for prior 6 months.

The clinical-problem solving case reviews useful pointers about portal hypertension and in particularly noncirrhotic portal hypertension.  Vitamin A is a rare cause of noncirrhotic portal hypertension.

Other causes of noncirrhotic portal hypertension:

  • Prehepatic level: portal vein or splenic vein thrombosis, splanchnic arteriovenous malformation
  • Intrahepatic level: hepatic vasculitis, HIV infection, infiltrative disease, and medications
  • Posthepatic: Budd-Chiari syndrome, IVC obstruction, restrictive cardiac disease.
  • Worldwide, schistosomiasis is the most common reason.
  • When other causes have been excluded, idiopathic noncirrhotic portal hypertension may be diagnosed, “especially in patients with chronic infection, thrombophilia, and immunologic conditions such as SLE.”  In one series of 69 patients, the diagnosis of idiopathic noncirrhotic portal hypertension was delayed for more than a year in 25% of cases and 7% received an erroneous diagnosis of cryptogenic cirrhosis.

Other points:

  • When ascites is due to cirrhosis, other signs of liver disease are typically present, including jaundice and laboratory findings (low albumin, coagulopathy, hyperbilirubinemia) as well as absence of cirrhosis on biopsy.
  • Serum retinol levels poorly reflect total body stores of vitamin A (& was normal in this patient)
  • Vitamin A supplementation in appropriate doses can prevent blindness in areas where food stores are not secure.  But, consuming excessive doses can lead to being a case report.

Related blog posts:

Mural, Old town San Juan

Mural, Old town San Juan

Excess Childhood Salt Intake Associated with Obesity

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A recent study (C Grimes et al. 24-h urinary sodium excretion is associated with obesity in a cross-sectional sample of Australian schoolchildren  British Journal of Nutrition  Volume  115 / Issue 06 / March 2016, pp 1071 – 1079) was summarized at AJP.com.au: Childhood salt intake linked to obesity.

An excerpt:

The study also found that in both four-to-seven-year olds and eight-to-12-year-olds, the prevalence of abdominal obesity was also higher in children with a higher intake of salt.

The recent findings published in the British Journal of Nutrition came from the SONIC (Salt and Other Nutrient Intakes in Children) study that measured salt intake in 666 primary schoolchildren aged four to 12 years….

“We found that 70% of Australian children are eating over the maximum amount of salt recommended for good health.

“In this study children were eating on average six grams of salt a day, which is over a teaspoon, and they should be aiming to eat about 4-5 grams a day.

”For every additional gram of salt children ate this was associated with a 23% greater likelihood of being overweight or obese. Such high intakes of salt are setting children up for a lifetime risk of future chronic disease such as high blood pressure and heart disease”

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21 Year Data for Cancer Survivors

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Most pediatric gastroenterologists see many children with pediatric cancers, so it is gratifying to see data showing improving long-term outcomes (GT Armstrong et al. NEJM 2016; 374: 833-42).  In addition, pediatric oncology serves as a model for improving therapy by enrolling virtually all of its patients in research protocols.

The authors evaluated late mortality among 34,033 patients in the Childhood Cancer Survivor Study.  All of these patients had survived at least 5 years after childhood cancer. During the study which had a median followup of 21 years, there were 3958 deaths and 1618 (41%) of these were attributable to health-related causes, including subsequent neoplasms (n=746), cardiac (n=241), and pulmonary (n=137).

The improvement in treatment regimens have included reductions in radiotherapy and anthracycline exposure.  The graph below shows survival rates 20 years after being cancer-free (15 years after being cancer-free for 5 years).

My take: This study confirms that these improved regimens have long-lasting effects on mortality.  Through cooperative research, we can do better in oncology and in all of pediatrics.

Incidence of death from any cause from patients treated between 1970-1999.

Incidence of death from any cause from patients treated between 1970-1999.

Bad News Bili

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A study (BL Schneider et al. J Pediatr 2016; 170: 211-7) from ChiLDReN (Childhood Liver Disease Research Network) shows that infants with biliary atresia whose total bilirubin (TB) does not drop below 2 mg/dL (34.2 microM) at anytime during the first 3 months after hepatoportoenterostomy (HPE) (Kasai) are at high risk for disease progression.

Key findings:

  • 68/137 (50%) had TB <2.0 at some point following HPE.
  • In the cohort with TB ≥ 2.0, the odds ratio for liver transplantation or death was 16.8.  Higher TB was associated with diminished weight gain, coagulopathy, and hypoalbuminemia
  • In the cohort with TB ≥ 2.0, transplant-free survival at 2 year occurred in only 20% compared with 86% in the TB <2.0 group
  • Interestingly, only 6.6% had variceal bleeding among the entire cohort by age 2 years.

The TB was associated with multiple other parameters of worsening liver function, indicating that TB is not the only measure to affect the decision of liver transplantation.

My take: About half of all patients following a Kasai were at high risk for early progressive liver disease.  TB ≥ 2.0 is a useful indicator of high risk.

Related blog posts:

Walnut Street Bridge, Chattanooga

Walnut Street Bridge, Chattanooga

Adrenal Insufficiency due to Fluticasone in Eosinophilic Esophagitis

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A recent study (MC Golekoh et al. J Pediatr 2016; 170: 240-5) shows that adrenal insufficiency developed in 10% of patients on chronic (>6 months) swallowed corticosteroid therapy for Eosinophilic Esophagitis (EoE).

Background: 58 patients with 67% receiving fluticasone and 33% receiving budesonide.  Median age: 13.7, median fluticasone dose 1320 mcg/day, median treatment duration: 4 yrs.  For budesonide, median dose was 1000 mcg/day and median age 10.7 yrs.

Key findings with low-dose ACTH stimulation:

  • Abnormal peak cortisol (≤ 20 mcg/dL) present in 15% and adrenal insufficiency (< 18 mcg/dL)  (n=6) noted in 10%
  • Only patients receiving >440 mcg/day of fluticasone had adrenal insufficiency
  • No patients taking budesonide had an abnormal cortisol level

Commentary:

  • Higher doses of fluticasone, particularly early in treatment, has been shown to have an improved inflammatory response.  However, as with asthma therapy, higher doses increase the risk of adrenal insufficiency.
  • Adrenal insufficiency can be asymptomatic but pose a risk for life-threatening adrenal crisis.
  • Strengths of study: Fairly large cohort, endoscopic/pathologic reports available, and ACTH stimulation testing which has better sensitivity than random cortisol.
  • Limitations: Lower number of patients receiving budesonide, particularly at a higher dose.  No indication of adherence.

My take: If higher doses of fluticasone are needed for prolonged period, consider screening (endocrinology consultation) for adrenal insufficiency.

Related blog posts:

Farjado, Puerto Rico

Farjado, Puerto Rico

CDC Guideline for Prescribing Opioids for Chronic Pain

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Full Text: CDC Guideline for Prescribing Opioids for Chronic Pain—United States, 2016

D Dowell et al. JAMA. Published online March 15, 2016. doi:10.1001/jama.2016.1464 .

Excerpts:

  • No evidence shows a long-term benefit of opioids in pain and function vs no opioids for chronic pain with outcomes examined at least 1 year later (with most placebo-controlled randomized clinical trials ≤6 weeks in duration).

  • Extensive evidence shows the possible harms of opioids (including opioid use disorder, overdose, and motor vehicle injury).

  • Extensive evidence suggests some benefits of nonpharmacologic and nonopioid pharmacologic therapy, with less harm.

CDC: “We know of no other medication routinely used for a nonfatal condition that kills patients so frequently,”

1st Six Recommendations (12 total)

1. Nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred for chronic pain. Clinicians should consider opioid therapy only if expected benefits for both pain and function are anticipated to outweigh risks to the patient. If opioids are used, they should be combined with nonpharmacologic therapy and nonopioid pharmacologic therapy, as appropriate. (Recommendation category: A; evidence type: 3)

2. Before starting opioid therapy for chronic pain, clinicians should establish treatment goals with all patients, including realistic goals for pain and function, and consider how opioid therapy will be discontinued if benefits do not outweigh risks. Clinicians should continue opioid therapy only if there is clinically meaningful improvement in pain and function that outweighs risks to patient safety. (Recommendation category: A; evidence type: 4)

3. Before starting and periodically during opioid therapy, clinicians should discuss with patients known risks and realistic benefits of opioid therapy and patient and clinician responsibilities for managing therapy. (Recommendation category: A; evidence type: 3)

4. When starting opioid therapy for chronic pain, clinicians should prescribe immediate-release opioids instead of extended-release/long-acting (ER/LA) opioids. (Recommendation category: A; evidence type: 4)

5. When opioids are started, clinicians should prescribe the lowest effective dosage.  (Recommendation category: A; evidence type: 3)

6. Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids and should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids. Three days or less will often be sufficient; more than 7 days will rarely be needed. (Recommendation category: A; evidence type: 4)

Other points:

  • Avoid concurrent benzodiazepines
  • Review state prescription drug monitoring program to look for dangerous combination therapies and prior opiod dosing
  • Consider risk mitigation strategies (eg. naloxone)
  • Suggests urine screening at start to screen for illicit substance abuse which increases risk

USAToday’s review of these guidelines: CDC issues new guideline on opiods

Bottomline: This report is very important for those who prescribe opiods for chronic pain.

Law Library, Univ of Michigan

Law Library, Univ of Michigan

Why GMO labels are a bad idea

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I was pleased to see the March 11 USAToday editorial: Our view: GMO Labels Feed Unwarranted Fears

Excerpt:

“Mandatory labeling …on balance it’s a bad idea. A key reason is that it validates the notion that genetically modified organisms (GMOs) are dangerous, which is simply not true.  Using science to make crops more resistance to drought or insects builds on the ancient practice of selectively breeding plants…Doing this in a lab at the genetic level makes it faster, more precise, and more effective.  But…harder for nonscientists to grasp…the European Union found that GMOs ‘are not per se more risky than…conventional plant breeding.’…75% to 80% of foods contain them.”

“The risk from mandatory labeling is the same as any action that ignores science and plays to unfounded fear.”

Related blog posts:

Walnut Street Bridge

Walnut Street Bridge

Drug Waste Costing Billions. Who benefits? Pharmaceutical Companies

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From NY Times: Waste in Cancer Drugs Costs $3 Billion a Year

Here’s an excerpt:

The federal Medicare program and private health insurers waste nearly $3 billion every year buying cancer medicines that are thrown out because many drug makers distribute the drugs only in vials that hold too much for most patients, a group of cancer researchers has found…

If drug makers distributed vials containing smaller quantities, nurses could pick the right volume for a patient and minimize waste…according to researchers at Memorial Sloan Kettering Cancer Center, whopublished a study on Tuesday in BMJ…

“Drug companies are quietly making billions forcing little old ladies to buy enough medicine to treat football players, and regulators have completely missed it,” said Dr. Peter B. Bach, director of the Center for Health Policy and Outcomes at Memorial Sloan Kettering and a co-author of the study…

Some non-cancer drugs also generate considerable waste, includingRemicade, an arthritis drug sold by Johnson & Johnson for which an estimated $500 million of the drug’s $4.3 billion in annual sales comes from quantities that are thrown away, researchers found.

My take: this is another indictment of our pharmaceutical companies willful neglect of medication costs or cynical manipulation of our healthcare system.

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Why Georgia Cannot Provide More Healthcare

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RE: Georgia Senate Resolution 756.

From Jay Bookman: Ga. can’t afford health care for its people, but tax cuts? Sure!..

Here is an excerpt:

Medicaid cannot be expanded in Georgia, extending much-needed health insurance to some 400,000 of our fellow citizens, because the state budget is under too much strain.

Sure, expanding Medicaid would save lives and improve the quality of life for many others, many of them lower-income working people whose jobs don’t include health coverage. Sure, it would bring billions of new federal dollars into the state and help rescue a health-care delivery system that is now collapsing in much of rural Georgia. Sure, it would create thousands of jobs, and sure, federal tax money would no longer be flowing out of Georgia to subsidize Medicaid coverage for people in other states…

Yet on Monday, a supermajority of the state Senate voted to slash the state income tax by an amount roughly equivalent to that needed to fund Medicaid expansion.

Related blog posts:

My day on the beach is about to get worse

My day on the beach is about to get worse. Flamenco beach.

European Experience with Biosimilars

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While there are numerous concerns regarding the use of biosimilar products, the preliminary experience with biosimilar infliximab has been favorable.

Full text link: European Experience of Infliximab Biosimilars for IBD (Gastroenterology & Hepatology)

Key points:

  • Biosimilars are leading to cost reductions of 30-40%.  In addition, to lowering the cost of infliximab, this is leading to reductions in costs for adalimumab and vedolizumab which are competing as 1st line therapies.
  • In the authors study of the first 210 patients, they did not find any difference in terms of immunogenicity or side effects.  In addition, efficacy was comparable to the ‘originator’ drug.

My take: Infliximab and adalimumab have been blockbuster medications for pharmaceutical companies, in part because they provide a great clinical benefit.  However, if biosimilars are truly biosimilar, the cost reductions will result in their widespread adoption.

Related blog post: Biosimilars -Position Statement  GutsandGrowth  This position statement: “Treatment of a child with sustained remission on a specific medication should not be switched to a biosimilar until clinical trials in IBD are available to support the safety and efficacy of such a change”

Castillo San Felipe del Morro

Castillo San Felipe del Morro