The Indispensable Physician

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A recent pair of commentaries (RM Wachter, L Goldman. NEJM 2016; 375: 1009-1011, R Gunderman. NEJM 2016; 375; 1011-13) provides some insight into what has been gained and what has been lost with the proliferation of hospitalist care in the past 20 years.

The growth of hospitalist care has developed due to numerous factors:

  • evidence of cost savings/better outcomes
  • need for rapid evaluation of acutely ill patients/repeated evaluations which would be disruptive to efficient outpatient physician practices

Decline of comprehensive care:

  • at times of extreme vulnerability when admitted to the hospital, patients have a physician assigned to them who they have probably never met.  This has led to a diminishment of the patient-physician relationship.
  • increasing number of physicians creates opportunities for miscommunication, particularly on admission and discharge, but also at every step of hospital care during “handoffs”

The second commentary, in particular, challenges the way medicine is evolving.  This article stresses the central role of the physician as opposed to the hospital filling that role.

“The reality is that medicine can be practiced without hospitals, but hospitals cannot function without physicians.”

The goal of developing personal relationships with our patients is often at odds with work-life balance.  Thus, having hospitalists and other ways of having cross-coverage, when we are unavailable, often conflict with being able to provide the best care.

My take (from 2nd commentary): “The true core of good medicine is not an institution but a relationship — a relationship between two human beings.”

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Glacier Nat'l Park

Glacier Nat’l Park

 

Newborn Bilirubin Measurements To Identify Biliary Atresia

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It is remarkable how tricky making a diagnosis of biliary atresia can be, even when one has seen the presentation many times.  For parents and many providers, one of the pitfalls includes the inability of recognizing acholic stools. To identify biliary atresia, promotion of stool color cards, over the last two decades, has not been very effective. To address this problem, a recent study (S Harpavat et al. JPGN 2016; 62: 799-803) describes the use of direct or conjugated bilirubin measurements in the newborn period. This study was conducted between 2009-2011.

As with previous studies, 35 infants with biliary atresia all had elevated direct bilirubin. In the non-biliary atresia group, 8936 of 9102 infants had direct bilirubin measurements within the laboratory’s reference range.  Thus, this study suggests that newborn direct bilirubin has a sensitivity 100% and specificity of 98.2%.

In a related publication, the same group published a letter to the editor (NEJM 2016; 2016; 375: 605-6) that describes a prospective two-stage screening of newborns for biliary atresia.  Of 11,636 infants included over a 15-month period, 121 were identified who had direct-bilirubin >95% reference interval in their laboratory.  At a median of 14 days, 11 remained abnormal: 2 had biliary atresia.  Overall, they state the net sensitivity was 100%, then net specificity of 99.9%, and the positive predictive value was 18.2%.

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Sullivan's Island, SC

Sullivan’s Island, SC

Biotin Supplementation and Thyroid Laboratory Results

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Biotin, which is a water-soluble vitamin, is given in several genetic conditions and often used as a supportive treatment in mitochondrial disorders.  A recent report (S Kummer et al. 2016; 375: 704-6 Letter to Editor) noted six children ages 1 mo-9 yrs with markedly abnormal thyroid studies who were receiving biotin.  The results mimicked Graves’ disease with high free thyroxine levels, low thyrotropin levels, and elevated anti-thyrotropin receptor antibodies.

After stopping biotin, these biochemical abnormalities resolved in 48 hrs for free T4/TSH and 7 days for anti-thyrotropin receptor antibodies.

My take: High-dose biotin can create concerning laboratory profile of Graves’ disease. Awareness of this phenomenon is important for endocrinologists and pediatric gastroenterologists as well.

Glacier Nat'l Park

Glacier Nat’l Park

Small Pediatric IBD Studies …Briefly Noted

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G Wahbeh et al. JPGN 2016; 63: 348-51.  This retrospective case series with 4 children  (aged 12-17 years) indicated that 2 had a ‘clinical response’ to ustekinumab therapy, though one of these had ongoing elevation of CRP.  The dosing may have been too low: 90 mg at week 0 and 4, then every 8 weeks.  My take: This study shows that ustekinumab’s use in pediatric IBD seems to be a ‘shot in the dark’ given the lack of coherent data.

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L Zimmerman et al. JPGN 2016; 63: 352-56. Among a cohort of 123 children who had underwent a bowel resection, from 1977-2011, the overall postoperative complication rate was 13%.  This included 3 of 24 who had prior infliximab and 9 of 99 who had not received infliximab. It is noteworthy that the infliximab group had more corticosteroid exposure. The authors concluded that preoperative infliximab was not associated with increased complications but noted that their sample size was small. My take: Studies of adults with Crohn’s disease have yielded conflicting results on whether preoperative infliximab increases the risk of complications.  This study shows that children likely have a lower rate of postsurgical complications and more pediatric specific data are needed.

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Latest on Tofacitinib for Refractory Ulcerative Colitis

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From Gastroenterology & Endoscopy News July 2016: Tofacitinib Effective in Refractory and Severe UC

An excerpt:

Tofacitinib (Pfizer), an oral agent already approved for certain patients with rheumatoid arthritis, can induce clinical remission in up to 25% of individuals with moderate to severe, refractory ulcerative colitis (UC) and clinical response in as many as 60% of these patients.

The results, based on two placebo-controlled trials involving more than 1,100 patients, showed the drug also increased the risk for serum lipid elevations but was otherwise safe. Researchers presented the data at the 2016 annual meeting of the European Crohn’s and Colitis Organization (ECCO; oral presentation 019)…

The new data are from the OCTAVE Induction 1 and Induction 2 trials, identically designed, randomized, double-blind and placebo-controlled Phase III studies…In the OCTAVE 1 trial, 476 patients received 10 mg of tofacitinib orally twice daily for eight weeks and 122 received an oral placebo. In OCTAVE 2, 429 and 112 patients were randomized to receive the two regimens, respectively.

Screenshot from gastroendonews.com

Screenshot from gastroendonews.com

Also from Gastroenterology & Endoscopy News August 2016: Update on Diagnosis and Treatment for Ulcerative Colitis  This article provides a succinct summary regarding diagnosis and treatments of ulcerative colitis; treatments discussed include emerging therapies like tofacitinib.

 

Early Preview of Basic Science Review: Biliatresone

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Generally, one of the best lectures at our national meeting is the “Basic Science Year in Review.”  I would be surprised if a recent study (O Waisbourd-Zinman et al. Hepatology 2016; 64: 880-93) does not get some attention during this review.

Even though biliary atresia (BA) remains the leading cause of pediatric liver transplantation, the exact reasons for its development have not been elucidated.  There are data “implicating both immune dysregulation and genetic factors in human BA.  Toxin-induced BA is not inconsistent with these findings and may represent a primary injury, with immune dysregulation representing a secondary insult.”

One of the reasons for suspecting a toxin dates back to outbreaks of a BA-like disease in newborn lambs that occurred in New South Wales in 1964 and 1988. During both these periods, severe droughts led to pregnant livestock grazing on atypical flora.  Ultimately, a plant toxin termed “biliatresone” was isolated from Australian plants (Dysphania species).

Here’s how this study advanced the science on biliatresone:

  • The authors treated mouse cholangiocytes in 3D spheroid culture and neonatal extrahepatic duct exlplants with biliatresone and compounds that regluate glutathione (GSH)
  • The authors determined the effects of biliatresone on SOX17 levels and the effects of Sox17 knockdown on cholangiocytes in 3D culture

Key findings:

  • “Biliatresoe caused disrupton of cholangiocyte apical polarity and loss of monolayer integrity.”
  • “Neonatal bile duct explants treated with the toxin showed lumen obstruction with increased subepithelial staining for α-smooth muscle actin and collagen, consistent with fibrosis”
  • “Biliatresone caused a rapid and transient decrease in GSH…and caused a significant decrease in cholangiocyte SOX17, and Sox17 knockdown in cholangiocyte spheroids mimicked the effects of biliatresone.”
  • These findings are easiest to appreciate in their figures, particularly Figure 4 and 5.

While pregnant women are not likely exposed to biliatresone, the authors showed that the effects of the toxin on lowering GSH was sufficient for cholangiocyte injury.; in addition, they showed that “SOX17 is required to maintain the epithelial architecture of the gallbladder and the cystic duct.”  Thus, there are likely other exposures that could lead to similar outcomes

My take: I will let Dr. Barnard explain the elegant experiments.  This study strongly supports maternal dietary factors as a contributing role in the pathophysiology of BA.  Now identifying these teratogens is crucial.

Also noted: X Zhao et al. Hepatology 2016; 64: 894-907. This study “strongly support redox stress as a critical contributing factor in biliatresone-induced cholangioctye injury” in Zebrafish.  Specifically, the authors identified that gene transcripts involved in redox stress, particularly regarding glutathione were upregulated after exposure to biliatresone.

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Glacier Natl Park

Glacier Natl Park

What to Make of A Motility Study of Children with Orthostatic Intolerance

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While a recent study (A Darbari et al JPGN 2016; 63: 329-35) provides some interesting data regarding the potential origin of gastrointestinal symptoms in the setting of orthostatic intolerance, I cannot support their conclusion that antroduodenal manometry (ADM) “should” be part of the evaluation of these affected children.

Background:

  • Retrospective study which included only subjects with a positive tilt test

What’s interesting:

  • Among 35 children with orthostatic intolerance due to either neurally mediated hypotension (NMH) or postural orthostatic tachycardia syndrome (POTS), ADM was abnormal at baseline or during tilt table testing in 26 (75%).
  • ADM studies were more often abnormal than gastric emptying studies, which were normal in 12 or 25.
  • Specific findings included neurogenic intestinal dysmotility in 15, antral hypomotility in 4, visceral hyperalgesia in 2, and regurgitation in 5.
  • GI symptoms of nausea, abdominal pain or vomiting were reproduced during tilt testing in 31 of 35 patients (89%).

Based on the discussion, the authors imply that ADM testing could help determine if the symptoms are due to neurogastrointestinal pathology or if normal, could indicate a central origin for the GI symptoms.  Thus, they conclude that motility testing “should” be part of comprehensive” orthostatic intolerance evaluation.

I would argue that this study does not show that ADM testing can reliably distinguish whether symptoms are due to a neurogastroenterological pathology or central pathology. And, in fact, there are better tests to examine for central origin.  I wouldn’t be surprised if many of their subjects had brain imaging, though this is not reported.

In addition, the authors acknowledge that ADM testing may not influence therapeutic decisions.  “The clinical response to promotility agents in children with POTS is generally low.”

My take: This study provides a useful mechanistic explanation of symptoms associated with orthostatic intolerance.  However, “I’m not there yet” on supporting ADM for all children with OI.

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Avalanche Creek Lake, Glacier Natl Park

Avalanche Creek Lake, Glacier Natl Park