What is FHH?Familial hypocalciuric hypercalcemia (FHH) is a very rare genetic condition that causes high blood calcium levels. It does not cause symptoms, and does not need to be treated. But be careful! Most of the time, high blood calcium is due to parathyroid disease, not FHH. The distinction matters, because the treatment is very different (do nothing for FHH, surgery for parathyroid disease). Most of the time, when we see someone who is diagnosed with FHH, he or she actually has a parathyroid tumor and needs an operation.
FHH is very rare. If you have high calcium levels, the odds are that you have a parathyroid tumor, and not FHH.
If you have high blood calcium and low urine calcium, then you very likely have a parathyroid problem and need a parathyroid operation, and the doctor who told you that you have FHH is making an error in this diagnosis. This page will help you learn more about FHH, and learn why your doctor could have made this mistake. As a background, the authors of this page (the doctors at the Norman Parathyroid Center) consult on over 4000 patients with high blood calcium every year (about 50 times more than anybody else). We have removed parathyroid tumors from many people diagnosed with FHH incorrectly by a doctor who means well, but is confused because of old teachings about urine calcium levels. If your doctor never mentioned FHH, then please don't read this page, it can confuse you (it means you have a good endocrinologist). If your doctor said "Your urine calcium level is low so I think you have FHH and you don't have primary hyperparathyroidism", then it is very likely he/she is wrong and this page is absolutely for you. We see thousands of patients every year with high blood calcium, and we see a real case of FHH about once a year. So we've seen over 40,000 cases of high blood calcium and just a handful of cases of FHH. If your calcium is high, and your PTH is above 35, the overwhelming odds are that you have a parathyroid tumor and your doctor is wrong--you do not have FHH. This is important because if you have a parathyroid tumor you need an operation to remove it--if you have FHH, then avoid surgeons--an operation will not help you. Before we dive into this topic let us say one more piece of background so you understand how common this misdiagnosis of FHH problem is: We give all of our patients a photo of their parathyroid tumor--but the reason we started taking photos of parathyroid tumors is so we could send the photos to the endocrinologists who thought that patient had FHH--proving they had a parathyroid tumor not some rare genetic disorder that few doctors will ever see in their entire careers. FHH is rare! Trust us folks, 95% of the people reading this page who were told "you have FHH" do not have FHH -- you have a parathyroid tumor and a doctor that is confused. Download the CalciumPro Parathyroid Diagnosis App. It will tell you if you have primary hyperparathyroidism or FHH.
FHH: What is FHH?
FHH is the abbreviation for a genetic medical condition called: Familial Hypocalciuric Hypercalcemia or: Familial Hypercalcemic Hypocalciuria
- Familial = occurs in multiple members of the same family (it is a genetic disease)
- Hypocalciuric = low amount of calcium in your urine
- Hypercalcemia = high amount of calcium in your blood
Thus, FHH is a very rare disease that runs in families which is associated with a higher than normal amount of calcium in the blood and a lower than normal amount of calcium in the urine. It causes no problems, so you don't do anything about it. People with FHH have high calcium levels their entire lives -- it is normal for them.
FHH can also be called: Familial Benign Hypercalcemia.
FHH almost always causes zero symptoms and zero problems, and therefore,
FHH does not require treatment. We don't do anything about FHH.
Why then all the fuss? Who cares? Well the problem is that MOST people with high calcium in the blood (about 99% of people with high calcium in the blood) have a disease called primary hyperparathyroidism which is caused by a tumor of one of the parathyroid glands. This DOES cause symptoms, and doing nothing about primary hyperparathyroidism will decrease your life expectancy, increase your chances of stroke and heart attacks, cause osteoporosis, and increase your chances of several cancers (breast, colon, prostate). See our page on the symptoms of hyperparathyroidism. So it is very important to separate out those people who have hyperparathyroidism and need an operation to feel better and to preserve their health, from those with FHH who need nothing done because nothing is "wrong".
Why all the fuss? Because the vast majority of people who are told they have FHH do not have FHH, they have a parathyroid tumor and it will slowly destroy their bodies while everybody sits back and does nothing. It is vitally important to differentiate FHH from hyperparathyroidism if your blood calcium is high. Keep reading and we will show you how this is done.
Difference in Symptoms Between FHH and Primary Hyperparathyroidism.
|Increased Cancer Risk||No||Yes|
|Hair Loss (women)||No||Yes|
Note this is a partial listing of symptoms simply to show that FHH doesn't have symptoms and hyperparathyroidism does. We have an entire page on the symptoms of primary hyperparathyroidism.
Thus, there are two potential causes of high blood calcium: 1) primary hyperparathyroidism (99.99%), and 2) FHH (0.001%). For those with primary hyperparathyroidism, removing the parathyroid tumor that is causing the disease will cure the disease (for ever). You will feel better and live longer. For those with FHH, the high calcium is not caused by a parathyroid tumor so removing a parathyroid gland won't help. If you really do have FHH, then parathyroid surgery is not only unnecessary but also inappropriate.
As stated at least 10 times already, almost everybody who is told they have FHH does NOT have FHH. They have a doctor who doesn't know how to tell the difference. We cannot over stress this, and this is the only reason this page is on this website--because at least 95% of people who are told they have FHH and therefore should avoid an operation are being given bad advice (life threatening advice) based upon outdated tests and assumptions.
Diagnosing FHH: How Do We Diagnose FHH? Where do the Doctors Go Wrong?
It has been taught since the 1960's that the only way to tell the difference between primary hyperparathyroidism and FHH is to measure the amount of calcium in the urine. We knew back then that this extremely rare disease ran in families (almost every person in the family has calcium problems, they all have high blood calcium levels their entire lives, or most of their lives), but there was no way to check a person's DNA for the bad genetic code (like we can do today--discussed below). So, for decades, endocrinologists were taught that when a patient came into their office with high blood calcium the first thing they were going to do was to measure the amount of calcium in the urine. If the calcium in the urine was high, the patient had a parathyroid tumor (and needed an operation to remove the parathyroid tumor) and if the calcium in the urine was low the patient had FHH and needed to avoid an operation.
What is low? Who decides what "low" urine calcium levels are? Well somebody somewhere 45 years ago said that a urine calcium below 100 mg/24 hours is abnormal (less than 100 mg of calcium found in a urine sample collected over 24 hours). So the old-time, out-dated rules are:A) if your blood calcium is high and your urine calcium is below 100 you have FHH, B) if your blood calcium is high and your urine calcium is over 100, you have hyperparathyroidism.
NOTE You will see that this is a dumb rule, and THIS is the mistake that the doctors are making. It's the arbitrary number of 100 that is causing all the troubles and mistakes!
Let's look at our most recent 10,000 patients that we operated on AND REMOVED A PARATHYROID TUMOR. Each dot on this graph represents a patient with high blood calcium. They all had primary hyperparathyroidism which is not in doubt because they had an operation where a parathyroid tumor was removed from their neck and after the operation they no longer had high blood calcium.
The vertical axis shows the blood calcium level, showing that the majority (but not all) patients with primary hyperparathyroidism have blood calcium levels above 10.1 mg/dl. The horizontal axis shows the amount of calcium in the urine of these 10,000 patients (always measured over a 24 hour period). The first thing that you will notice is that the 10,000 dots are completely random; they flow consistently from very low urine calcium levels to very high urine calcium levels. The second thing you see is that patients with parathyroid tumors can have very low urine calcium levels, medium (normal) urine calcium levels, or very high urine calcium levels. The third thing that you can see is that patients with parathyroid tumors who have very high blood calcium levels are NOT more prone to have high urine calcium levels (patients with higher blood calcium levels do not have a higher propensity to have high urine calcium levels). And finally, notice that we colored the dots red and blue, with red dots representing patients with primary hyperparathyroidism due to a parathyroid tumor in their neck who had calcium kidney stones, while the blue dots represent those patients with a parathyroid tumor but they do not have kidney stones. You can easily see that patients with parathyroid tumors can have kidney stones regardless of their blood calcium levels, and regardless of their urine calcium levels. Said differently, you cannot predict which patients with primary hyperparathyroidism will get kidney stones based upon how high their blood calcium levels are or how high their 24-hour urine calcium levels are.
This is the same graph but we removed all the patients who had a 24-hour urine calcium level of less than 100 mg. If the decades-old teachings were right and the level of 100 was accurate in determining who had FHH and who had primary hyperparathyroidism then the graph would look like this. Of course this is absurd. The number 100 is simply arbitrary because it is a nice round number, but the real world is not this simple. The data clearly shows that patients with primary hyperparathyroidism don't naturally fall with a nice grouping above the number 100. They fall with a nice grouping from way down around 20 to way up to 1000 (as seen in the first graph). The problem is the arbitrary number of 100--it is simply dumb. So if your doctor told you that you have FHH because your 24-hour urine calcium is below 100, then he/she is wrong.
It is IMPOSSIBLE to tell the difference between FHH and primary hyperparathyroidism based upon the results of a 24-hour urine test.
NOTE: these graphs are included in the CalciumPro Parathyroid Diagnosis App. You can learn more about parathyroid problems and interact with the graphs on this page on your iPad or Android device. If you are reading this far on this page, then you may want to consider the CalciumPro app, it will save you from getting silly, unnecessary tests and wasting your time.
The third graph in this series shows 418 patients (out of 10,000 = 4.2%) that we have operated on for primary hyperparathyroidism and removed a parathyroid tumor. Some of them had doctors who knew they had a parathyroid problem even though their 24-hour urine was less than 100. Importantly, 306 of these 418 patients (74%) were told that they had FHH and that they should not have a parathyroid operation because they did not have a parathyroid tumor--simply because their 24-hour urine calcium was less than 100. The patients either sought the advice of a different endocrinologist, or they (and their primary care doctor) figured it out for themselves and the patient was appropriately referred for surgery.
Every patient represented by the red and blue dots on this (third) graph had primary hyperparathyroidism but their 24-hour urine calcium was less than 100 mg/24 hours. One fourth of these folks had a doctor who disregarded the dumb cut-off of 100, while the other three-fourths were WRONGLY given the diagnosis of FHH. A different doctor then sent them for surgery (or they sent themselves!).
It is IMPOSSIBLE to tell the difference between FHH and primary hyperparathyroidism based upon the results of a 24-hour urine test.
Another important point that is made clear by the third graph is that there are lots of patients here that have kidney stones. As you will recall from the blue symptom table at the top of this page, patients with FHH do not get kidney stones, but patients with primary hyperparathyroidism can get stones. You simply cannot differentiate between FHH and primary hyperparathyroidism based upon the amount of calcium in the urine.
The next graph shows the 24-hour urine calcium results for the same 10,000 patients with primary hyperparathyroidism. This time we present the data in a bar graph so you can see how often patients with a parathyroid tumor actually have a 24-hour urine test with a result less than 100. It happens 4.2%, thus one out of 20 people with primary hyperparathyroidism will have a low 24-hour urine test, and if their doctor doesn't know better, he/she will tell the patient that they have FHH and they do not. Remember from above, this is very important because FHH is a "nothing" problem (you don't do anything about it because it causes no problems), whereas primary hyperparathyroidism causes lots of problems, lots of symptoms, and will slowly destroy a patient's body and overall health.
As shown in this blue bar graph, it is clear that many endocrinologists are figuring out that the 24-hour urine test has little (or no) value in evaluating patients with primary hyperparathyroidism. We have over 500 different endocrinologists refer patients to our center every year, with over 1,750 endocrinologists in our database (who have sent us at least one patient). Because our patients come from all over the country (and not one part of one city), we get to observe what the endocrinologists around the country (and around the world) are doing in their office when a patient with high blood calcium comes to see them. In the year 2000, 79% of the patients that were sent to us for surgery had a 24-hour urine test performed (they made the patient pee in a jug and collect their urine for 24 hours). By 2005 the number of patients referred to us who had a 24 hour urine test prior to surgical referral had decreased to 56% (p<0.0001). The trend has continued, with only 37% of the patients referred to us in 2010 having had a 24-hour urine test (p<0.0001). Thus, two-thirds of endocrinologists no longer obtain a 24-hour urine test on their patients--they have learned that the arbitrary number of 100 mg of calcium in the urine has no meaning. (Note, if you want to read more about this, then our advanced diagnosis page is for you. This is advanced stuff, for doctors and patients who are really getting into this).
Genetic Testing for FHH.
OK, so now we all understand that almost all people who have high blood calcium will have a parathyroid tumor in their neck and this high calcium is not normal for them. They have not had high calcium their entire life... they had normal calcium levels (typically in the mid 9's) their entire life until they grew a tumor on one of their parathyroid glands. The parathyroid tumor makes too much parathyroid hormone which in turn takes calcium out of the bones and puts it into the blood. The high blood calcium in these folks came from their bones! These people get symptoms, they get sick, they get bad osteoporosis, they get kidney stones, they get high blood pressure, they get all sorts of bad things happening because of the high calcium and PTH in their blood.
In contrast, a very small minority of people with high calcium in their blood (extremely rare) will have FHH. This means it is normal for them to have this slightly higher blood calcium. They don't get sick. They don't get osteoporosis or stones. They just have a higher "normal" calcium level in the blood. (I remind you, we've seen one case in over 20,000 cases of high blood calcium).
So if FHH is a genetic disease, we should be able to use modern technology to examine a patient's DNA to find the bad gene that is responsible for this "higher normal" blood calcium level. And yes we can. There are several companies now that can do this test for you. Two things to remember, 1) it is not cheap, and 2) it is not always correct either! Most of the times the results will say "moderate probability of FHH", or "high probability of FHH". See, even these genetic tests are not always correct (because they have "control" DNA in their database that came from people with primary hyperparathyroidism but were misdiagnosed as FHH because of a urine calcium level below 100! How crazy is that?!). Even the companies that do the genetic testing will tell you that 10% of patients with FHH will not have a genetic defect. Of course they wont! Because they don't have the friggin disease! They have primary hyperparathyroidism with low urine calcium and their doctor has made a mistake in their diagnosis!
FHH Technical Genetic Information
Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant condition caused by mutations in the calcium sensing receptor gene (CASR). FHH is characterized by hypercalcemia, hypocalciuria, hypermagnesemia, and normal to low levels of parathyroid hormone (PTH).
FHH is caused by loss-of-function mutations in the CASR gene. To date over 100 different alterations in the CASR gene have been described. Many of these cause diseases of abnormal serum calcium regulation. Inactivating mutations result in undersensing of Ca(++) concentrations and consequent PTH overproduction and secretion. This leads to either familial hypocalciuric hypercalcemia (FHH) or neonatal severe primary hyperparathyroidism (NSPHT), depending on the severity of the functional impairment. Homozygous or compound heterozygous loss-of-function mutations in CASR result in neonatal severe hyperparathyroidism (NSHPT) a severe and possibly lethal condition. Symptoms appear in infancy and include extreme hypercalcemia, failure to thrive, hypotonia, skeletal demineralization, and severe parathyroid hyperplasia. Some de novo mutations may cause a mild or transient version of NSHPT. Treatment may require parathyroidectomy in these very young infants.
Except for a very small percentage of cases with no apparent CASR mutations (maybe because they don't have the disease?), FHH is due to heterozygous inactivating CASR mutations. Serum calcium levels are mildly-to-moderately elevated (never above 11.0). Parathyroid hormone (PTH) levels are within the normal range, phosphate is normal, and urinary calcium excretion is low for the degree of hypercalcemia. In contrast to patients with primary hyperparathyroidism, the majority of FHH patients do not seem to suffer any adverse long-term problems from their high blood calcium (hypercalcemia).
Calcium Clearance to Creatinine Clearance Ratios:
Patients with apparent mild-to-moderate hyperparathyroidism, who have a ratio of calcium clearance to creatinine clearance that is <0.01, could possibly have familial hypocalciuric hypercalcemia (FHH). Identification of a heterozygous inactivating CASR mutation confirms this diagnosis, while identification of novel alteration(s) increases the likelihood of a FHH diagnosis, but does not confirm it until family studies or functional studies support the diagnosis. Absence of any mutations or the presence of polymorphism(s) that are known to be functionally neutral makes the diagnosis very unlikely.
Approximately 20% of FHH patients are reported to have calcium to creatinine clearance ratios of >0.01 (editorial comment: Many of these patents do NOT have FHH, they have primary hyperparathyroidism). These patients can be difficult or impossible to distinguish from individuals with primary hyperparathyroidism (PTH).
Companies Providing Genetic Testing for FHH
FHH is very rare, so if your doctor says you have it based only upon the amount of calcium in your urine, then you almost certainly do not have it. The only way to know for sure is to get a genetic testing of your DNA to see if you have the gene for FHH. Even this genetic testing is wrong about 15% of the time. There are several companies that provide genetic testing for FHH. Athena Diagnostics is a leader in the field of genetic testing for endocrine diseases. Ambry Genetics is also a very reputable company for genetic testing for FHH.
FHH vs Primary Hyperparathyroidism: The Bottom Line
Bottom line is this: If your blood calcium is high, the odds are that you have a parathyroid tumor that is causing primary hyperparathyroidism. Genetic testing is used to diagnose FHH - urine calcium should never be used for diagnosis. Most of the time, if you have FHH, then other members of your family will have it as well.
Remember, many people diagnosed with FHH do not have FHH. If your doctor says you have FHH based only upon your urine calcium level, then demand a genetic test. The diagnosis of FHH should never be made without a genetic test. And then, know that most genetic tests for FHH will be equivocal and they will not come out and say yes/no.