Exploring Vitamin D Deficiency and Related Disorders

Welcome to PICU Doc On Call, A Podcast Dedicated to Current and Aspiring Intensivists.

I'm Pradip Kamat and I'm Rahul Damania and we are coming to you from Children's Healthcare of Atlanta - Emory University School of Medicine in Atlanta, GA.Today we are going to present a case of a 3 year old presenting with bilateral hyper-flexed wrists.

Here is Rahul with our case:

A 3 yo previously healthy M presents to the emergency department after his mother noted his wrists becoming completely stiff and flexed. Despite several attempts to stretch out his wrist, his mother was unable to place them back into position. She brought him to the ED for further evaluation. Importantly, mother denies any trauma or injury. Mom notes that this happened once before one month ago. The episode lasted 10 min and self-resolved. She did not seek medical attention at that time. Patient has no history of bleeding, bruising or chronic medical conditions. His immunizations are UTD. Family hx was relatively unremarkable however the mother states that she gets admitted to the hospital for Kidney Stones 4-5 times per year. She usually follows with a urologist. Though she is on diuretic therapy for recurrent renal stones, she denies that her son has any access to these medications & also denies any ingestion. She does state that patient is a picky eater and does not drink milk but will eat cheese often with 4-5 cups of juice. Mother denies any recent upper respiratory tract symptoms, vomiting, constipation, urinary abnormalities or changes in gait.

Upon presentation to the ED, his vital signs were stable. His physical exam is normal except for Bilateral hands in flexion with digits on flexion as well. After some resistance the examiner was able to extend hands. There were no abrasions or signs of cutaneous injury in his bilateral hands. Full range of motion of elbow and shoulder as well as full range of motion of ankle and knee as well as hip. Prior to drawing blood for a diagnostic work-up the patient undergoes an EKG which shows some artifact but is notable for a prolonged QTc interval of 560.

To summarize key elements from this case so far, we have a toddler with

• Bilateral hyper-flexion of the wrists which seem to be in a tonic state and is recurrent
• A family history of renal metabolic disease.
• and finally, an EKG abnormality.
• Rahul one key pertinent negative at this stage is that there is no trauma & patient has full range of motion at other large joints
• Rahul, let's transition to key history and physical elements when you think about bilateral wrist flexion.

1. This is an interesting chief complaint, however I would tailor my history to assess for trauma as this seems to be a primary MSK issue.

• The key feature here is that the patient has bilateral wrist involvement which brings up the concern for an underlying systemic cause such as an electrolyte abnormality, connective tissue disorder, or muscular abnormality. The family history of recurrent kidney stones points more towards a familial renal or electrolyte problem.
• I would ask about any trauma related to skin wounds. As this patient is in a tonic state, I would worry about tetanus.
• I would also get a good dietary history as excessive juice consumption may have limited nutritional value.

1. On physical exam, I would look for any other MSK abnormalities with this bilateral wrist flexion. Especially if we are heading down the route of nutritional abnormality, electrolyte disturbance or renal anomaly, I would like to assess for any bowing of the legs, joint flaring, any metacarpal shortening, or rib abnormality.

Pradip, I would love to hear more about the emergency room diagnostic work-up in this patient...

• To continue with our case, the patients labs were consistent with:
• A very low ionized calcium of 2.2 (normal 4.4-5.4mg/dl). Also, his total serum Ca was low — < 5mg/dL (Nl range 8.9-10.4mg/dl) with a relatively normal albumin.
• His CMP was notable for an elevated Alkaline Phosphatase at 963 with normal liver function and bilirubin.
• The rest of his electrolytes, renal function, and CBC were normal. As the primary concern was regarding calcium homeostasis, a PTH was sent and revealed a markedly elevated value of 823 pg/mL and his 25 Vitamin D level was low at 3.6 ng
• A urine Ca:Creatine ratio was elevated and finally a radiological joint survey of wrists showed osteopenia, physeal widening consistent with the final impression bringing up concern for rickets.
• The patient was given 60mg/kg of calcium gluconate and was transferred to the PICU for closer diagnostics & monitoring in the setting of severe hypoCa.

OK to summarize, we have:

• A 3 year-old M with bilateral hyper-flexed wrists due to severe hypocalcemia in the setting of hypovitaminosis D.
• Rahul Let's start with a short multiple choice question very relevant to PICU:
• A 5 year boy is admitted PICU with acute respiratory failure secondary to poly-trauma sustained after being involved in a motor vehicle collision in which the boy was an unrestrained passenger. After initial resuscitation with normal saline, the patient received rapid infusion of 4 units of packed red cells for hemorrhagic shock and a Hgb of 3gm% over a very short period of time. The patient is started on phenytoin for seizure prophylaxis due to traumatic brain injury. After initial resuscitation and stabilization, the patient develops an abnormal rhythm on the monitor and is now hypotensive. His blood gas drawn post transfusion is notable for a metabolic alkalosis and an ionized ca of 2. The hypotension and abnormal rhythm improves with IV repletion of calcium gluconate.
• The most likely explanation for the patients hypocalcemia is
• A. Pancreatic injury
• B. Citrate chelation of Ca
• C. Sepsis
• D. Phenytoin
• The correct answer to this question is (B) Citrate Chelation of Serum CaCitrate intoxication is a frequent complication after massive blood transfusions and often presents itself as metabolic alkalosis. The reason this term comes about is due to the conversion of citrate, which is applied as an anticoagulant in blood bags, to bicarbonate, and this conversion happens, predominantly in the liver. So, Stored blood is anti-coagulated using citrate (3 g/unit of RBC), which chelates calcium.
• Typically a healthy adult, the liver metabolizes 3 g of citrate in 5 min. Infusion rates greater than 1 unit of RBC over 5 min, or liver dysfunction, increase citrate concentration and lowers plasma ionized calcium.
• To highlight our other answer choices, we do not have enough evidence to suggest that there is injury to the pancreas at this stage and acute pancreatitis does not cause hypocalcemia this quickly. Although in a relatively subacute setting, acute pancreatitis can lead to hypocalcemia. This is primarily due to auto-digestion of mesenteric fat by activated pancreatic enzymes resulting in release of free fatty acids which form calcium salts, transient hypoparathyroidism and hypomagnesemia.
• While hypocalcemia can be seen in sepsis and critical illness in general and the etiology is usually multifactorial. In sepsis, the effect of the bacteremic state and the inflammatory mediators on PTH secretion and function can result in hypocalcemia.
• Phenytoin is known to cause hypocalcemia by altering the bone and mineral metabolism. It increases impairs normal Vitamin D metabolism, which in turn lowers the calcium absorption from gut and causes hypocalcemia. This effect is unlikely to be seen with use of phenytoin in a patient with normal renal function.

Before we go into diagnostic management, I want to particularly highlight some physiologic aspects of Ca homeostasis:

Only 1% of totally body Ca is in the extracellular volume. 99% of the body's calcium is in the bone. the ECF ca exists as protein bound (mostly albumin) (~40%), 10% as chelated and 50% as ionized. Ionized Ca is the active form of Ca.

Serum Ca is tightly regulated by PTH, vitamin D, and calcitonin by their action on the gut, kidneys and bone.

Actions of PTH: In the kidney PTH inhibits phosphate reabsorption (remembered as Phosphate Trashing Hormone) and promotes phosphaturia. This loss of phosphate shifts flow of Ca from bone to the ECF.

PTH also facilitates distal tubular reabsorption of filtered Ca. PTH also production of 1,25-dihydroxy Vitamin D to facilitate intestinal absorption of calcium and phosphate. Thus PTH helps increase serum ca and decrease serum phosphate.

Calcitonin: secreted in response to increased serum ca, helps divert Ca to the bones (remembered by "tones the bones"). It promotes calciuria and phosphaturia.

An increase in serum pH of 0.1 unit can cause ionized Ca++ to fall by 0.16mg/dl. The total ca will drop 0.8mg/dL fro every 1gm/dL decreases in serum albumin. The change in total Ca and ionized ca are independent of each other.

• As we have talked about a few presentations of hypocalcemia thus far as well as calcium homeostasis — but I do want to highlight some subtle but clinically relevant findings in hypocalcemia, namely petechiae - this is because Ca is integral in platelet metabolism and when you have low ica, platelets will have decreased activation and thus you will have physical exam findings related to primary hemostasis. Second, remember that hypocalcemia in neonates may present as stridor.
• 'LETS CONCLUDE OUR PODCAST WITH DIAGNOSTIC WORK-UP & MANAGEMENT FRAMEWORKS. If you had to work up our patient with hypocalcemia, what would be your diagnostic approach?
• Rahul one way to approach any patient with hypocalcemia is to measure serum PTH level. You can then divide causes associated with elevated PTH level & causes associated with low PTH levels.
• In general when serum Ca is low, PTH level should go up by triggering release of Ca and phosphate from the bones as well as absorbing Ca from the kidneys. PTH also will trigger formation of 1,25 dihydroxyvitamin D formation which increases intestinal absorption of Ca and phosphate.
• So if you have have Hypocalcemia and a high PTH level: think of PTH resistance, calcium loss or calcium intake/absorption problems. PTH resistance (endorgan resistance, missense mutations in PTH or hypomagnesemia). Pseudohypoparathyroidism (X-linked dominant) can present with physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. Patients with PTH resistance usually have high serum phosphate levels.
• Ca loss can be acute (sepsis, acute pancreatitis, TLS and even respiratory alkalosis) OR Chronic causes include renal disease, hyperPhosphatemia and metastases.
• A common cause of poor calcium uptake and poor management of calcium homeostasis is deficiency of or resistance to vitamin D.
• Hypocalcemia and Low PTH level: Can be congenital as in DiGeorge syndrome or acquired causes such as HIV infection, autoimmune, destruction of PTH glands after surgery or radiation. Infiltration of gland with cancer, sarcoidosis, or iron or copper deposition.
• Alright listeners, this can be very confusing with arrows etc. so lets summarize with a conceptual framework. Remember PTH physiologically increases Ca concentration and decreases Phosphate concentration. So if you have hypoparathyroidism, which means that your PTH levels are low, you will have hypoCa & hyperPhosphatemia. With calcium homeostasis disorders take it back to the normal parathryoid axis and then branch out from there
• Exactly Rahul, so how does Vitamin D get integrated into this pathophysiologic or diagnostic framework?
• Vitamin D Deficiency: Could be genetic or acquired: Enzyme deficiencies or Vitamin D receptor problems.
• Common causes include: obesity, malabsorption, and poor exposure to sunlight and problems with nutritional intake which also could be important given "picky eating" behavior in our patient. A toddler typically doesn't consume non dairy sources of calcium (beans/green leafy vegetables)-thus exacerbating poor calcium absorption caused by Vitamin D deficiency. Babies who breast feed and are not supplemented with Vitamin D, those who are premature or if mother had Vitamin D deficiency- can also have Vitamin D deficiency.
• I do want to call out Vitamin D deficiency 2/2 malabsorption as this is frequently tested on boards in the context of cystic fibrosis and the exocrine insufficiency which can occur along with Celiac disease where you get VIt D insufficiency due to intestinal failure.
• Exactly Rahul, whether you're talking about PTH or Vitamin D, to be comprehensive, A good approach for labs would be to send some basic labs such as CBC, CMP, Urine analysis, blood gas, ionized calcium. Labs such as ionized Ca, serum calcium, magnesium, potassium etc help to fix abnormal values quickly which should be the # 1 priority while a search for diagnosis is being made.
• A consult with endocrine as well as nephrology services may help with other labs that need to be sent. The help of our friendly PICU nutritionist is invaluable to get detailed dietary history as well as to make dietary suggestions.
• Let's go into the clinical relevance of these labs which you will get...
• Labs to determine underlying cause include:
• PTH: Key value to investigating cause of hypocalcemia as we have described above.
• Serum phosphate: High level indicates end organ resistance or renal disease. Low value with high PTH suggests secondary hypoparathyroidism such as Vit D deficincy.
• Alkaline phosphatase- a bone turnover marker (elevation in patient with hypocalcemia suggests vitamin D deficiency),
• 25-hydroxyvitamin D (major circulating form of vitamin D and best marker of vitamin D status).
• The blood 25-hydroxyvitamin D level corresponds with vitamin D intake and activity; the half-life of 25-hydroxyvitamin D is 2 to 3 weeks, as compared with a half-life of 4 to 6 hours for 1,25-dihydroxyvitamin D. (hence 25-hydroxy Vit D is measured).
• amylase, lipase(for suspected pancreatitis), CPK (if suspect muscle breakdown), urine ca:creatinine ration (to determine abnormal renal calcium excretion and renal tubular reabsorption)
• Adrenocorticotropin, cortisol, and thyroid-stimulating hormone, for suspected polyendocrine failure
• Rahul we mentioned in our case the imaging and EKG as part of the presentation, what are salient points with regards to these diagnostic tests?
• Imaging studies: x-ray of metaphysis of a long bone (such as wrist or knee). Hand images may show shortened fourth and fifth metacarpals and suggest pseudohypoparathyroidism type 1a. In hypoparathyroidism, skull x-ray may show intracerebral calcifications (such as basal ganglia calcifications). Chest radiograph to evaluate for rachitic rosary.
• EKG: Prolonged QT interval on electrocardiogram as a result of ST-segment lengthening.
• Consult with genetics if there is suspicion for a genetic cause.
• In our patient: The total as well as serum ionized ca are low. there is appropriately elevated PTH as well as alkaline phosphatase, normal serum phosphate level, low 25 hydroxy vitamin D points to severe Vitamin D deficiency due to poor nutritional intake. (Nutritional Rickets)
• If our history, physical, and diagnostic investigation led us to hypocalcemia due to Vitamin D deficiency what would be the management frame work?
• Initial focus should be on providing good basic PICU care. Attention to airway, breathing and hemodynamics should be a priority in such patients.
• Before diving into diagnostics, every attempt to correct abnormal values must be made and the levels frequently reassessed.
• Calcium: If symptomatic or severe, EKG changes: can use 10% calcium gluconate or calcium chloride as boluses followed by calcium gluconate infusion, which should be titrated to maintain normal serum ionized ca levels.
• Remember listeners that ca is a divalent cation so which other divalent cation would you want to also make sure is within reference range in your hypocalcemia management? You got it, magnesium. If patient has hypomagnesemia -correct magnesium concurrently, since hypocalcemia is refractory until magnesium deficiency is corrected.
• You got it! So shifting back to our ca replacement management approach once patient can tolerate PO, they should be given calcium carbonate.
• For patient with vitamin D deficiency or hypoparathyroidism: Supplementation with Vitamin D analogues: 1,25-dihydroxycholecalciferol (calcitriol), or Vitamin D3.
• One thing to watch for as this childs calcium normalizes is the "hungry bone syndrome" a condition in which there is paradoxical worsening of hypocalcemia after initiation of vitamin D therapy. This condition is thought to be due to rapid bone-mineral uptake by the demineralized skeleton, and management may require very high doses of calcium, as well as occasional therapeutic doses of calcitriol (1,25-dihydroxyvitamin D), the active form of vitamin D.
• How do we follow up on such patients and monitor their response to therapy: Follow blood levels of calcium, phosphate, 25-hydroxyvitamin D, PTH, and alkaline phosphatase and the urinary calcium:creatinine ratio approximately 4 weeks after the initiation of treatment and at monthly intervals until resolution of laboratory abnormalities. Most children will show improvement in about 3 months of their radiological abnormalities.
• Pradip where can our listeners read more information about hypocalcemia ?
• Rahul I would highly recommend that our listeners read the Case by Virkud Y et al published in NEJM 2020 (N Engl J Med 2020;383:2462-70. DOI: 10.1056/NEJMcpc2027078)
• Also chapter 71 page 126-pages 877-878 of the latest edition of Furhmanns and Zimmerman's textbook of Pediatric Critical care has information on hypocalcemia.
• Chapter 30, pages 930-933 Lucking et al. Pediatric Critical care Text and Study Guide Second edition volume 1.
• These references will be in the show notes

Alright to summarize today's take home points — remember that when you have hypocalcemia you care going to be twitchy. Remember the mnenonic CATS go NUMB which reviews the...