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Hypercalcemia in Sarcoidosis - 8/29/2012

posted Aug 29, 2012, 8:01 AM by Rohit Das   [ updated Dec 27, 2012, 6:58 AM by Purnema Madahar ]

Our last conference of the month…very bittersweet. Aman was kind enough to present another case today, this time with Dr. Lief, centered around a patient presenting with hypcalcemia and renal failure, ultimately diagnosed with sarcoidosis. We’ve encountered our arch-nemesis earlier this month, in the context of uveitis. We’ve also talked about hypercalcemia, in the setting of primary hyperparathyroidism. We’ve also had multiple discussions about renal failure…So, let’s try to bring these concepts together.

In the setting of non-PTH mediated hypercalcemia with concurrent lung disease, granulomatous disease is very likely, with Sarcoidosis and Tuberculosis being the most common causes.

  • Hypercalcemia is relatively common in sarcoid patients, occurring in 10-20% of patients. Hypercalciuria is more common, occurring in up to 50% of patients.
  • The mechanism is not completely understood, but it is thought to be due to unregulated production of 1,25-Hydroxy (activated) Vitamin D by rebellious macrophages. This leads to increased intestinal absorption of calcium, and thus, hypercalcemia.
  • Interestingly, there is some literature to support that hypercalcemia with sarcoidosis worsens with sunlight, which may explain our patient’s presentation in August! However, as the attached article states, one would expect that this would then be more common in the more “sunny” states, which isn’t the case.

The patient presented today also came in a creatinine of 3.0, which was 0.9 the last time it was checked in 2008. The true prevalence of renal disease in sarcoidosis is not completely clear, but retrospective studies based on biopsy series report a prevalence of 30-50% - so, it’s pretty common. Most of the renal disease with sarcoid is in relation to associated effects of hypercalcemia.

  • Due to hypercalciuria, nephrolithiasis is one of the more common manifestations of renal disease. It occurs in 15-20% of patients, and can be the presenting manifestation in 2-4%. Chronic hypercalciuria can also lead to distal, type I, RTA (a topic for another daily…). Consequent acidification of the urine also promotes stone formation.
    • In 2008, Aman’s patient actually presented with a symptomatic stone (though serum calcium was normal at the time) to the ED, and had a CT Scan, which showed diffuse abdominal lypmphadenopathy…I think I hear the sound of a ball dropping
  • Hypercalcemia also leads to a defect in the concentrating ability of the kidney, which is due to multiple postulated mechanisms, including decreased sensitivity to ADH mediated aquaporin chennels as well as reductions in Na absorption in the loop of Henle. This leads to polyuria, dehydration and volume depletion. Hypercalcemia also leads directly to renal artery vasoconstriction, further compounding this issue.
  • Finally, and probably most importantly, long-standing hypercalcemia can also lead to nephrocalcinosis – deposition of calcium oxalate/phosphate stones within the renal tubules and interstitium. Though reported in 15% of patients with sarcoid, in patients with sarcoid and CKD, nephrocalcinosis is the cause in 50% of patients. With treatment, nephrocalcinosis does not commonly lead to ESRD.
  • Sarcoid can also lead to calcium independent causes of kidney disease, including granulomatous interstitial nephritis – though this is common (up to 40%), it does not generally lead to kidney dysfunction. Glomerular disease can also occur with sarcoid, though this is relatively rare as compared to what’s mentioned above.

Regarding management, other than treatments for hypercalcemia itself, which we’ve talked about, the treatment of sarcoid-related hypercalcemia is as usual – steroids.

  • An important point, though, is to make sure you have the right diagnosis before breaking out the big guns. Steroids can partially treat lymphoma (potentially impacting yields for biopsy), and is definitely a bad idea in the setting of TB.
  • With 20-40mg/day of prednisone, serum calcium normalizes in most patients within 3-5 days, and hypercalciuria resolves with 7-10 days. In patients who can’t tolerate steroids, anti-malarial drugs (which decrease inflammation and macrophage related production of activated Vitamin D) such as choloroquine are potential options. Interestingly, ketoconazole, which inhibits the cytochrome P450 system and also decreases calcitriol production, also has some literature behind it for patients who can’t tolerate, or don’t respond to, steroids.
Dr. Lief also mentioned how we're beginning to better understand the genetics and inflammatory physiology of sarcoidosis in recent years, and I've attached two references related to that topic.

Also - I wanted to correct myself on a recent blurb on diuresis in edematous states. After getting some feedback, I realized that I was incorrect, which is probably what I deserve for trying to talk about physiology...anyway,
  • Nephrotic syndrome, due to "underfilling" as a result of hypoalbuminemia, DOES lead to a sodium retaining state, which itself also contributes to edema. In this respect, salt restriction, diuresis and consequent natruesis is valuable in treating the edema.
  • However, I think I implied that through this process, diuresis improves GFR. That is wrong :(...
  • Though, with gentle diuresis (1-2L/day), diuresis is unlikely to worsen renal dysfunction, due to the balance provided by mobilizing interstitial fluid...I think that was my point...
I've attached an article on this subject, which hopefully sheds a light on this issue. Unfortunately, it's a pdf of a full text webpage article, but anyway...

It’s been a fun month and really enjoyed doing these dailys. I’ve learned a lot, and hope you guys have too. Given the intern/resident transition, the weekend, and Labor Day, the daily will be taking a bit of a hiatus. It’ll be returning back on Tuesday for some medicine goodness…keep on reading!!

Vitamin D, Calcium, and Sarcoidosis
Sharma, CHEST 1996, Volume 109: 535-49

Casella et. al., J Am Soc Nephrol 1993, Volume 3: 1555-62

Altaf et. al., Am J of Med Sci 2000, Volume  319(1): 25

Courtesy of Dr. Lief -- 
Bargagli et. al., Clin Chest Med 2008, Volume 29: 445-458

Muller-Quernheim et. al., Clin Chest Med 2008, Volume 29: 391-414