Missing ingredients in TPN -Case Report

Recently one of my radiology colleagues, Dr. Laura Hayes, put together (lead author) a presentation (poster) for an upcoming meeting.  The main focus of the presentation is a TPN-dependent toddler who presented with refusal to walk due to copper deficiency.

Attached is a link to the presentation: TPN Copper.  This link is a power point presentation with numerous radiographs and even bone scan images.

Key points:

  • All TPN components except dextrose have been in periods of shortage over the last few years.
  • TPN-dependent patients may not be receiving all the needed components and their physicians may not have been notified of the specific shortage(s).
  • Copper deficiency leads to reduced activity of numerous enzymes important for function of bone, blood, skin, nervous system and hair.
  • Subperiosteal hemorrhage leads to the periosteal thickening seen in this case and is associated with the bone pain our patient experienced.
  • Increased losses of bilious fluid can increase the risk of copper deficiency due to the excretion of copper in bile.
  • Other TPN-related deficiencies reviewed include thiamine deficiency (Wernicke’s encephalopathy), Vitamin D deficiency (Rickets), and Vitamin C deficiency (Scurvy).

Another recent case report:

Oestreich AE, Cole CR. Vigorous periosteal reaction secondary to copper deficiency in an infant on total parenteral nutrition. (2013) Pediatr Radiol 43:1411-1413.

Related Blog Posts:

From theory to bedside practice

“That’s fine in practice, but how does it work in theory?”

I heard this quote while visiting the University of Chicago. A recent (really cool) study reminded me of this quote because of the interplay between predictions of the effects of a genetic defect in bile acid conjugation and the actual clinical presentation of 10 pediatric patients  (Gastroenterol 2013; 144: 945-55).

Background: Bile acid synthesis from cholesterol requires 17 enzymatic reactions in different cellular compartments of the hepatocyte.  These steps are tightly regulated.  All of the steps are vulnerable to genetic defects, some of which have been recognized for a long time.  The final step occurs in the peroxisome and is 2-part mediated by bile acid-CoA ligase enzyme (SLC27A5) and bile acid-CoA:amino acid N-acyltransferase (BAAT). This latest study examines the final step of primary bile acid synthesis in which there is conjugation with amino acids. Conjugation of bile acids improves absorption of lipids including fat-soluble vitamins.

Results: Ten patients with severe fat-soluble vitamin deficiency (five with rickets) were carefully analyzed. Levels of urinary bile acids showed increased unconjugated forms (79%).  In addition, there was an absence of glycine and taurine conjugates in the urine, bile, and serum. In the 8 patients with duodenal bile analysis, >95% of bile acids were unconjugated which was too low for efficient lipid absorption. Typically, glycine and taurine conjugates account for >95% of bile acids secreted in bile.  On mass spectrometry, there was a marked presence of a dominant ion at m/z 407 which represents cholic acid.  The investigators also performed molecular analysis and identified mutations in BAAT in 7 of 8 who had available DNA.

Clinical features:

  • Hepatomegaly in 3 of 10
  • Age at diagnosis: 3mo-14 years
  • Elevated aminotransferase: 4 of 10
  • Low GGT
  • Liver failure/transplant in one patient
  • All 10 had fat-soluble vitamin deficiency
  • None had diarrhea (which had been theorized)

Thus, patients had variable liver disease ranging from none to severe.

Take-home message(s):

Specific genetic defects have been identified in the final steps of bile acid production. Abnormal urine mass spectrometry may increase the suspicion for mutations in BAAT (or SLC27A5).  Breakdown in any of these bile acid synthesis steps can lead to fat-soluble vitamin deficiency.  Potential treatment with primary conjugated bile acids (e.g.. glycocholic acid) should improve fat-soluble vitamin absorption in these patients.

Related blog links:

Common to be “D-ficient”

Many of the children that a pediatric gastroenterologist sees are at risk for Vitamin D deficiency, including children with inflammatory bowel disease, cystic fibrosis, celiac disease, and liver diseases.  In addition, vitamin D deficiency is widespread: in U.S. 50% of children aged 1-5 years and 70% 6-11 years are vitamin D deficient or insufficient. A thorough review on this “D-lightful” vitamin was in a recent JPEN (JPEN J Parenter Enteral Nutr 2012; 9S-19S).

History: In 1822 Sniadecki recognized children in urban but not rural Poland developed rickets. He postulated the effects of the sun as the reason for rickets; his idea was dismissed.  In 1920s, the concept of irradiating milk to prevent rickets emerged. In 1950s, outbreak of hypercalcemia in infants in Great Britain was thought to be related to vitamin D fortification and curtailed this practice in Europe.  However, these cases were likely due to Williams syndrome.

Sources of vitamin D: oily fish (salmon), cod liver oil, some mushrooms, egg yolk, & sunlight. Exposure of an adult in a bathing suit to one minimal erythemal dose (MED) is equivalent to ingesting 20,000 IUs of Vitamin D. (The minimal dose that induces any visible reddening at that point is defined as one MED.)

Effect of sunscreen: A sun protection factor (SPF) of 30 absorbs approximately 98% of solar ultaviolet radiation & thus lowers vitamin D production by 98%.

Ethnicity: Melanin is an effective SPF.  A person of african-american descent, on average, has an SPF of 15, which reduces vitamin D production by 90%.

Age: Aging decreases 7-dehydrocholesterol in human skin.  Due to this, the elderly produce much less vitamin D.  For example, a 70 year old has a 75% reduction compared to a 20 year old.

Forms of vitamin D:  25-hydroxyvitamin D (25OH-D) is the major circulating form of vitamin D & physicians measure 25OH-D. 25OH-D is metabolized in kidney to 1,25-dihydroxyvitamin D (1,25OH-D), also called calcitriol.  This is the most biologically-active and is responsible for increasing intestinal calcium absorption and mobilizing calcium from bone.  However, 1,25OH-D provides no information vitamin D deficiency; it can be elevated or normal in deficiency states.

  • Cholecalciferol (vitamin D-3) is formed in the skin from 5-dihydrotachysterol.
  • Ergocalciferol (Vitamin D-2) is the form in Drisdol (8000 IU/mL) & Ergocalciferol Capsules (1.25 mg =50,000 USP Units)

Vitamin D deficiency:  The exact numbers are debated.  The institute of medicine (IOM) has considered individuals deficient if 25OH-D is <20 ng/mL.  The Endocrine Society and the author suggest vitamin D deficiency as <20 ng/mL & insufficiency as <30 ng/mL.  The author recommends ideal levels between 40-60 ng/mL.

Consequences of deficiency:

Osteoporosis, Osteopenia, Rickets (see references below): Bone weakening occurs due to loss of phosphorus from the kidneys.  Vitamin D deficiency lowers accrual of calcium in skeleton and leads to osteoporosis, osteopenia, and rickets. Imaging for rickets: the best single radiographic view for infants and children younger than 3 years is an anterior view of the knee that reveals the metaphyseal end and epiphysis of the femur and tibia. This site is best because growth is most rapid in this location, thus the changes are accentuated.

Nonskeletal consequences: vitamin D deficiency is associated with increased risk for preeclampsia, URIs, asthma, diabetes (type 1), multiple sclerosis, hypertension, and schizophrenia.

Treatment:

  • Infants who are breastfed should be receiving supplemental vitamin D, 400 IU/day.
  • Adults/children (>1 year) RDA 600 IU/day –mostly from diet per IOM. Yet author states, “it is unrealistic to believe that diet alone can ….provide this requirement.”
  • In vitamin D deficient patients: (initial treatment) 2000 IU/day or 50,000 IU/week for 6 weeks.
Toxicity from vitamin D (from NEJM 2010; 364: 248-254.): “Toxicity from vitamin D supplementation is rare and consists principally of acute hypercalcemia, which usually results from doses that exceed 10,000 IU per day; associated serum levels of 25-hydroxyvitamin D are well above 150 ng per milliliter (375 nmol per liter). The tolerable upper level of daily vitamin D intake recently set by the Institute of Medicine (IOM) is 4000 IU.”

Additional references:

  • -Pediatrics 2008; 122: 398. Should give 400 IU/day to breastfed babies. Consequences of Vit D deficiency: increased risk for DM, multiple sclerosis, cancer (breast, prostate,colon), rickets, and schizophrenia. Article lists vit D content of foods (high in cod liver oil, shrimp, fortified milk, many fish). Severe deficiency when < 5ng/mL, deficient if < 15 ng/mL; probably should be >32 ng/mL. Causes of vit D deficiency: decreased synthesis (due to lack of sun -skin pigmentation, sunscreen/clothing, geography, clouds), decreased intake, decreased maternal stores & breastfeeding, malabsorption (eg celiac, CF, EHBA, cholestasis), increased degradation; treatment of rickets: double-dose of vitamin d (~1000 IU/day for babies & 5000 for older kids) x 3-4 months along with calcium (30-75/mg/kg/day). Follow Ca/phos/alk phos monthly. Alternatively, give ~100,000 units over 1-5 days.
  • -JPEN J Parenter Enteral Nutr. 2011;35:308-316-Results: The study included 504 IBD patients (403 Crohn’s disease [CD] and 101 ulcerative colitis [UC]) who had a mean disease duration of 15.5 years in CD patients and 10.9 years in UC patients; 49.8% were vitamin D deficient, with 10.9% having severe deficiency. Vitamin D deficiency was associated with lower HRQOL (regression coefficient –2.21, 95% confidence interval [CI], –4.10 to –0.33) in CD but not UC (regression coefficient 0.41, 95% CI, –2.91 to 3.73). Vitamin D deficiency was also associated with increased disease activity in CD (regression coefficient 1.07, 95% CI, 0.43 to 1.71). Conclusions: Vitamin D deficiency is common in IBD and is independently associated with lower HRQOL and greater disease activity in CD. There is a need for prospective studies to assess this correlation and examine the impact of vitamin D supplementation on disease course.
  • -JPGN 2011;53: 361. similar prevalence of low Vitamin D as general population –58% with less than 32.
  • -JPGN 2011; 53: 11. Guidelines for bone disease with inflammatory bowel disease.
  • -Pediatrics 2010; 125: 633. Increasing Vit D deficiency noted in minority children. n=290. 22% w levels <20, 74% <30.
  • -Hepatology 2011; 53: 1118. Good vitamin D levels are another favorable predictive factor in antiviral response to Hep C along with IL28B.
  • -NEJM 2010; 364: 248-254. Vitamin D insufficiency. Levels between 20-30 may be OK -not enough evidence to determine conclusively whether this level is detrimental
  • -J Pediatr 2010; 156: 948. High rate among african americans with asthma, 86%. n=63.
  • -Pediatrics 2009; 124:e362. n=6275. 9% of pediatric patients vit D deficient & 61% were insufficient.
  • -Pediatrics 2009; 124:e371. n=3577. low 25OH-D levels inversely assoc with SBP/metabolic syndrome.
  • -NEJM 2009; 360: 398. case report of rickets
  • -J Pediatr 2003; 143: 422 & 434
  • -Pediatrics 2003; 111: 908. 200 IU Vit D recommended for all breastfed infants.
  • -J Pediatr 2000;137: 153 & 143.. Nutritional rickets–primarily in blacks; rec vitamin D 400 IU per day.