Ep 37: A 63-year-old with confusion

There's no focal findings on physical examination, and other than her mental status, there are no localizing neurologic findings. Cathy, what were your initial thoughts and the initial diagnostic maneuvers? (Cathy) Well, the differential diagnosis here is so broad, and it's really hard to narrow down at this point.

In situations like this, when I'm presented with these cases, I really just try and start broad, and the workup should be broad too, and you just try and get some clues to what system might primarily be involved. In her case, the history sounds like it's fairly acute over the last couple of days, and she doesn't have any localizing signs to make me think of a territorial stroke. So, I'm really more worried about an infection or metabolic derangement first.

So, I mean, we can really just start with a CMP and a CBC because that may be helpful in deciding the next steps. (Charlie) Okay. Her CBC is normal, but her metabolic panel is notable for a serum calcium of 14.8 mg/dL, along with minimal elevation of BUN and creatinine. (Cathy) Okay. Well, that really was helpful. So, she's presenting with hypercalcemia, and this is really an extreme presentation of hypercalcemia. So, it can definitely cause confusion and obtundation.

But, most often, it's asymptomatic, and we recognize it usually just on routine calcium measurements. Some patients may complain of vague neuropsychiatric symptoms, including trouble concentrating, personality changes, depression. But sometimes patients will also have peptic ulcer disease or nephrolithiasis. (Charlie) This sounds like pretty severe hypercalcemia. (Cathy) Yeah. It's definitely on the severe end of hypercalcemia.

And we start to see that with serum levels that are over 12 or 13 mg/dL, and she's surpassed that. So, her calcium is 14.8, so that's really high. And especially if it develops acutely, then you can get lethargy, stupor, coma, or more severe gastrointestinal symptoms, like nausea, anorexia, constipation, or even pancreatitis. (Charlie) Any comment on the elevated BUN and creatinine? (Cathy) Well, hypercalcemia decreases the renal concentrating ability, so that can cause polyuria and polydipsia.

But with her neurologic symptoms, she also is probably not accessing enough water, so she's likely volume depleted. Another thing to remember with hypercalcemia is that it can result in significant electrocardiographic changes. So, you can sometimes see bradycardia, sometimes AV block, short QT intervals, so you would want to check an EKG on this patient too. (Charlie) So, now that we know she has severe hypercalcemia, what do you think is causing that?

(Cathy) So, you need to think about the feedback loops that maintain calcium homeostasis, and this involves the parathyroid hormone, or PTH, which comes from the parathyroid glands, and the active vitamin D metabolite 1,25-dihydroxyvitamin D. So that comes via the kidneys. But then also remember the gut which absorbs the calcium, and then the bones which are the major storage facility in your body and can release a lot of calcium too.

(Charlie) So, you really have to think about the bones, the kidney, and the gut, as you're trying to understand the pathogenesis of hypercalcemia. (Cathy) Right, and the parathyroid glands as well. So, the most common cause of hypercalcemia in adults is excess PTH production or primary hyperparathyroidism. Although, usually, we don't see presentations that are this acute or this severe with calciums to this degree. (Charlie) So, what causes are you thinking of on this patient?

(Cathy) So, in this patient, I'd also been thinking about a primary malignancy. So, this can be over the parathyroid glands, so you can sometimes get parathyroid adenomas, or hyperplasia, or rarely carcinomas. In someone this age, you also have to think about hypercalcemia of malignancy, and this can either be from overproduction of PTH-related peptide or from lytic skeletal metastases.

So, some solid tumors will produce PTHrP and that shares homology with PTH in the first 13 amino acids, and it binds the PTH receptor. So, it mimics the effects of PTH on the bone and the kidney. And in PTHrP-mediated hypercalcemia of malignancy, the native PTH levels are suppressed by the high serum calcium levels. (Charlie) So, primary hyperparathyroidism and hypercalcemia of malignancy are the two top things on your differential then at this point.

(Cathy) Yeah. (Charlie) Okay. What about things further down your list, just for the sake of completeness? (Cathy) Hypercalcemia associated with granulomatous disease, for example, with sarcoidosis or lymphomas, is caused by enhanced conversion of 25-hydroxyvitamin D to the more potent 1,25-[di]hydroxyvitamin D. In these disorders, 1,25-[di]hydroxyvitamin D enhances intestinal calcium absorption and that results in hypercalcemia and suppressed PTH.

Now, besides metastases, there are other disorders that directly increase calcium mobilization from the bone, such as hyperthyroidism. Less likely causes of hypercalcemia would be exogenous calcium overload, as in milk-alkali syndrome or a total parenteral nutrition with excessive calcium supplementation. Now, both of those would cause decreased levels of PTH.

The other disorder on the differential for hypercalcemia that would cause an inappropriately elevated or normal PTH level is familial hypocalciuric hypercalcemia. Now, this is an autosomal dominant syndrome that's most commonly involving inactivating mutations in the calcium-sensing receptor, and these mutations impair extracellular calcium-sensing by the parathyroid glands and the kidneys, and that leads to inappropriate PTH secretion and increased renal tubular calcium reabsorption.

(Charlie) Okay. That sounds like a lot. But the differential of hypercalcemia really is an important differential for us to keep in mind. It sounds like the next reasonable lab test would be to start with the branch point of measuring the PTH level then, right? (Cathy) Yeah. That's the first branch point since that's the most common cause to consider, although malignancy is also a concern in this patient. So, I would also check the PTHrP. (Charlie) Okay. Well, let's get back to this patient.

Subsequent laboratory testing reveals a normal parathyroid hormone level, but an elevated parathyroid hormone-related protein level. So, we then went on to imaging, and the initial evaluation shows a chest radiograph with multiple nodules suggestive of metastatic disease. Unfortunately, the nephew does not know anything about his aunt's past medical history. He tells us that he was only in town visiting his aunt while he was attending a healing yoga conference.

The question asks about the various malignancies that can cause this syndrome.

And it's most common in cancers of the lung, head and neck, skin, esophagus, breast, GU tract, for the solid tumors. And then if you think about the heme malignancies, you see it often in multiple myeloma-- remember that high calcium is one of the CRAB criteria-- and also in lymphomas. (Charlie) Which of these will cause an elevated PTHrP? (Cathy) Yeah, so that's the key to this question.

So, all of the solid tumors that are mentioned in the question-- so breast cancer, lung cancer, the head and neck cancer, and bladder cancer-- can all cause PTHrP. We talked before about how hypercalcemia from lymphoma tends to be via vitamin D conversion and not from PTHrP protein production. So, in this patient, who we know has multiple metastases in her lungs and an elevated PTHrP, the least likely cancer we would find would be mantle cell lymphoma.

(Charlie) Great. Okay. So, the teaching point of this case is that severe hypercalcemia can present with altered mental status or other neurologic findings. It may be caused by an elevation of PTH-related protein emanating from solid tumors, typically from the breast, lung, head and neck, or even the bladder. Lymphoma can also cause hypercalcemia, but that's via a different mechanism that relates to elevated levels of vitamin D and, therefore, gut absorption.

(Cathy) And if you want to read more about this, you can check out Harrison's chapter on Oncology and Hematology. But also within the Cardinal Manifestations of Disease, there's a chapter on hypercalcemia. ♪ (music) ♪