Our guest blogger, Dr. Kevin Parrack a surgeon from the Norman Parathyroid Center educates us about differentiating Primary Hyperparathyroidism (pHPT) from Familial Hypocalciuric Hypercalcemia (FHH) in a two-part series. Part 1 below discusses important differences between the two conditions. Part 2, scheduled to post later this month, focuses on the practical application of differentiating pHPT and FHH using a case study.

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When it comes to diagnosing primary hyperparathyroidism, there are a number of issues that have been debated over time. One of the tools that can be easily misunderstood is the urinary calcium test. This is a study that is broadly used but frequently misunderstood. It is used as an attempt to differentiate Primary Hyperparathyroidism (pHPT) from Familial Hypocalciuric Hypercalcemia (FHH, often referred to as FHH1).

WHY IS IT IMPORTANT TO DIFFERENTIATE? Patients with pHPT and FHH both typically have elevated blood calcium levels and parathyroid hormone levels (PTH) that are not normal for the corresponding calcium levels (either high or inappropriately at the higher end of normal). This is a problem because only a select few patients with FHH will benefit from having parathyroid surgery. Most will not have a change in their labs after surgery, nor will they have any clinical benefit. So it is important to differentiate the two in hopes of avoiding an unnecessary surgery on a patient with FHH.

WHY IS A URINARY CALCIUM TEST ORDERED? The idea behind the urinary calcium test is that most patients with primary hyperparathyroidism have a high urinary calcium level, and patients with FHH have a low urinary calcium level. So many doctors will order a 24-hour urinary calcium collection or calcium: creatinine clearance ratio as a standard test when they see blood labs consistent with primary hyperparathyroidism. The assumption is that if the urinary calcium level is below a certain threshold, then the patient likely has FHH and not pHPT. That can lead to a diagnosis of FHH and subsequently a recommendation for no surgery.

WHAT’S THE PROBLEM? As we will see, the problem with this pathway is that some patients with pHPT will be misdiagnosed with FHH, and this can lead to harm to these patients. There are a few factors regarding the urinary calcium collections that lead to this error in diagnosis.

• Some patients with pHPT can have very low urinary calcium levels. This is due to problems in vitamin D metabolism in the parathyroid patients.
• The error rate for the urinary calcium collections is higher than what would be considered acceptable in the blood labs, so erroneously low urinary calcium levels can be reported.
• FHH is extremely rare, so even though the above two issues are not common, the very low incidence of FHH means that the false positive rate of the urinary testing is relatively high.

This is not a minor problem for a patient who has pHPT.

We know that pHPT decreases a person’s life expectancy and can lead to symptoms that interfere with their quality of life.

Therefore if a patient has a urinary calcium level that is consistent with FHH, is then labeled with this diagnosis despite the fact that they have pHPT and does not have surgery, they may have a shorter, less enjoyable life. This is a problem we should avoid.

WHAT IS FHH? In order to understand what to do about the problem, we first have to understand FHH. Understanding certain nuances allows us to develop a plan that helps ensure that FHH is not diagnosed in error. We must balance the desire to avoid an unnecessary surgery in a patient with FHH against the goal of offering an indicated surgery to appropriate patients with pHPT.

FHH is a rare disorder caused by mutations in a gene for the calcium-sensing receptor (CaSR). This receptor is found in both parathyroid and kidney tissue where it is integral to maintaining a balance in the blood and urinary calcium levels. It is also found in many other tissues, including the bone and brain, and responds to more than just calcium, but we will keep our focus narrow.

WHAT DOES THE CALCIUM-SENSING RECEPTOR DO? On the parathyroid gland the CaSR allows the parathyroid gland to sense a low calcium and increase parathyroid hormone (PTH) production, or sense a high calcium and decrease PTH production. In the kidney the CaSR allows the kidney to respond to high blood calcium by excreting more calcium into the urine, or to respond to a low blood calcium by excreting less calcium in the urine.

In FHH the CaSR receptor is not working normally, which reduces the sensitivity of the receptor to calcium levels. Imagine being in a house where the thermostat registers the temperature lower than it really is. It would keep cranking up the heater even if the temperature in the house were normal or elevated. The results of a poorly functional CaSR is that a higher than normal calcium level is needed to stimulate the parathyroid glands to decrease PTH. So most patients with FHH will have a high calcium level and an inappropriately normal or elevated PTH level in their blood labs.

Similarly the kidneys are confused, they don’t realize the blood calcium is so high, so they keep trying to retain calcium in the blood, by preventing it from being excreted in the urine. The overall result is that the blood calcium goes up, the urine calcium goes down, and the PTH is higher than it should be. The PTH is normal, but not suppressed, in most FHH patients, high in others.

For most people with FHH it is a benign disease, causing no symptoms and no problems. With certain forms of FHH, kidney stones, bone problems, pancreatitis or other issues may be more likely than in the general population.

UNDERSTANDING FHH GENETIC MUTATIONS If the cause of this problem is a genetic mutation, understanding some of the details about these particular mutations can help us tell the difference between FHH and pHPT.

Most patients with FHH have one inactivating mutation in the gene that is responsible for CaSR. That means they have one normal CaSR gene, and one mutated CaSR gene that doesn’t work properly. Having just one non-working gene is enough to cause abnormal labs. Another way to say this is that people who are herozygous for CaSR non-functional mutations can develop FHH. This means that FHH is an autosomal dominant disorder.

In autosomal dominant disorders an affected person will have a parent who has the disorder and roughly 50% of the children of an affected individual will have the disorder. In other words in FHH families, about half the family will have FHH.

With all this information in mind we can now try and spot patients who might have FHH, and avoid suspecting it in patients who likely have pHPT, even if their urinary labs are consistent with FHH.

FHH PROFILE FHH patients are usually asymptomatic, with high calcium levels starting in childhood and persisting for life, have multiple hypercalcemic family members, usually with one or more family members who had parathyroid surgery that did not change their labs or symptoms.

Patients who have had blood labs consistent with primary hyperparathyroidism or FHH but do not have a story that matches the FHH profile, usually have pHPT. And avoiding an operation in these patients because urinary labs suggest FHH can hurt the patient.

WHAT ABOUT PEOPLE WHO DON’T KNOW THEIR FAMILY MEDICAL HISTORY? People who do not know their family history should be treated the same as people who know their family history does not include hyperpercalcemia. This is true because genetic disorders that cause hypercalcemia, including FHH, are so rare. Proper counseling is required, but refusing surgery based on urinary calcium testing alone in such patients can be an error. It is true that in this situation some FHH patients will wind up with a surgery that may not clinically benefit them, but if the surgery is done at a center with extremely low surgical risks, this is safer than not doing a surgery in a patient with pHPT that can lead to early demise or serious medical problems.

WHAT ABOUT PEOPLE WHO HAVE A STORY & FAMILY HISTORY THAT FIT FHH? What can be done to clarify the diagnosis in hopes of avoiding an unnecessary surgery? The first step is to get parathyroid blood panels and proper urinary studies on all family members with high calcium levels. The calcium : creatinine clearance ratio is better than the 24-hour total calcium level. While it is not perfect we see fewer mistakes with the ratio than the urinary calcium level test results. If all or nearly all hypercalcemic family members have blood and urine labs that are consistent with the biochemical FHH profile, then this is a reasonable diagnosis to consider. Genetic testing and counseling is appropriate, and if the diagnosis of FHH is confidently made, then surgery is unlikely to play a role. There is a subset of FHH patients who may benefit from surgery for whom expert selection and counseling is required before surgery is considered.

WHAT IF UNCERTAINTY PERSISTS? In some cases despite the best workup the diagnosis remains unclear. Doctors know there is an overlap in the urine studies between FHH and pHPT, and the genetic testing available is not infallible, nor are all related mutations characterized. For patients in whom the truth is not clear from the labs, careful counseling is required. If the odds that surgery will help is high enough some patients will choose surgery because they do not want to risk keeping a parathyroid tumor that could hurt them, and they want to know the truth. Others will choose not to have surgery because the risks and costs of surgery are not worth it to them. And for other patients the odds that surgery will help them is so low that surgery should not be offered.

I hope that this has helped answer more questions than it raises. I have operated on multiple patients who were diagnosed with FHH based on urinary studies but turned out to have parathyroid tumors. These patients were relieved to have their symptoms resolved and labs normalized by surgery. Through their own persistence they got the help they needed to be correctly diagnosed and avoid a life with uncured parathyroid disease. I balance this against the very few patients who I operated on that turned out to have FHH.

Dr. Kevin Parrack is a surgeon at the Norman Parathyroid Center, a high volume parathyroid practice that treats around four thousand parathyroid patients per year. In this role Dr. Parrack focuses on teaching patients and physicians about parathyroid disease in hopes that more people will become familiar with this problem and therefore fewer people will suffer from it without appropriate treatment.

Dr. Parrack obtained his undergraduate degree at NYU before graduating from Stony Brook School of Medicine. He completed his residency program at Columbia Presbyterian in Manhattan and the endocrine surgery fellowship at the Cleveland Clinic. His focus on teaching began in college, where his first career was in test prep for the medical school entrance exam. Throughout his training Dr. Parrack worked on admissions and academic committees, designed curriculums and teaching aids, and that interest carried into his role as a surgeon. Before coming to the Norman Parathyroid Center Dr. Parrack was a faculty surgeon at Columbia where he was the director of the Thyroid Biopsy Center and managed outreach to the community to increase awareness regarding endocrine disease.