The Pregnancy Lab

Should there be a critical value for hCG test results?

A short while back, a colleague asked Ann and me if we were aware of any need to have a critical value for hCG tests.  Our colleague had been asked by a physician to implement one in his laboratory because the physician had “missed” a molar pregnancy diagnosis due to her being unaware of the hCG test result that had been performed by the lab.  The physician argued that if the lab had notified her that the hCG result was very elevated, it would have alerted her to the fact that this patient may have had an abnormal pregnancy.

Seems reasonable enough, right?  Maybe not.

Let’s first consider the definition of a “critical result.”  Strictly speaking, a critical result is a test result above (or below) a pre-determined cutoff that, if observed, would require immediate medical attention due to the threat of an adverse event (e.g. death) to a patient.

The selection and use of critical results is a giant issue in healthcare laboratory medicine.  Doctors order all kinds of tests on many different patients every day.  The results of those tests are most often delivered electronically through the use of integrated data networks.  The lab performs a test, reports the result via a computer network where it is delivered to the physician.  While the test result is likely to be informative to the care and treatment of a patient, the doctor doesn’t necessarily have to immediately know about the result.  A cholesterol test is a good example.  The result is informative and may guide treatment decisions but the decision to initiate or modify treatment isn’t urgent so the doctor doesn’t need any special notifications.  As such, it would be highly unusual for a lab to have a critical result notification in place for a cholesterol test.

Now consider a result of a blood glucose test.  There can be very serious medical problems if the concentration of glucose is too high (e.g. greater than 450 mg/dL) or too low (e.g. less than 50 mg/dL).  As such, labs have critical results for glucose.  If the concentration exceeds the critical cutoff then the healthcare provider is immediately notified so that appropriate interventions can take place to prevent medical harm to the patient.

While these two are examples are clear-cut, many others are not.  The result is that the lab struggles to find answers to several questions such as 1) What tests are considered “critical?” and 2) What is (are) the cutoff(s) to be used for tests that make the list?  The answers to these questions aren’t trivial.  If the list of tests includes those that aren’t truly critical to patient care then lab personnel spend a lot of time calling results of tests to doctors.  The same thing happens if the cutoffs aren’t selected appropriately.  Furthermore, not only are lab personnel affected, so too are the doctors whose time from caring for their patients is consumed answering those phoned results.

It’s not unusual for a physician to request that the lab add a test to the critical result list.  Frequently this occurs when the physician fails to notice a test result and made an inappropriate decision as a result.  That was the case with the molar pregnancy patient.  A molar pregnancy is an abnormal pregnancy without a viable fetus that usually results in a very elevated hCG concentration, often much higher than that seen in a normal pregnancy.  Women with molar pregnancies have to be treated to prevent potential malignant disease from developing.

While that may seem like a good reason for having a critical hCG test result it’s actually not.  That’s because there isn’t a single, useful hCG concentration above which a molar pregnancy can be easily differentiated from a normal pregnancy.  Some molar pregnancies have hCG concentrations that are more typical of normal pregnancies and some normal pregnancies can have hCG concentrations that are as elevated as they are with molar pregnancies.  There is too much overlap between the two types of pregnancies for an effective hCG cutoff to be established for use as a critical value.  The use of one would be chaotic and would likely result in extreme confusion between doctors, laboratories, and patients.  And in the delivery of any type of healthcare, confusion is definitely not a good thing.

Is the qualitative serum pregnancy test obsolete?

I’ve written several times about qualitative hCG tests in this blog.  As a reminder, qualitative tests can be performed using urine or serum samples.  Urine tests can be performed close to the patient or even at home because the urine sample requires no special processing.  However, when serum is the test really can’t be performed at home or at the point-of-care because the blood sample has to be centrifuged to first obtain the serum and centrifugation is usually only performed in the clinical laboratory.  Notably, clinical labs are often able to do quantitative hCG testing on serum, too.

So, if a lab can do qualitative and quantitative hCG testing on serum, why not just offer one test instead of two?  In other words, might the qualitative test be considered obsolete?  My lab recently published a study that addressed that question.

To answer that question we surveyed several hundred doctors and the survey results revealed the following:

1. When requesting serum hCG tests, 49% of physicians preferred to order a qualitative rather than a quantitative test even though they believed quantitative tests were more accurate.
2. Physicians preferred qualitative tests because they believed that they received the test results faster.

However, when we examined the turnaround time data, that last point was not supported.  There are a few definitions of turnaround time to consider.  Doctors consider it to be the time it takes to get a result after the sample is collected while laboratorians consider it to be the time it takes to produce the result after they receive the sample.

By the lab’s definition, qualitative tests were performed more rapidly than quantitative tests but there were no differences using the doctors' definition of turnaround time.  That’s because the time it takes to transport the sample to the laboratory is known to contribute the most to delays in the total testing process.  So, although physicians believed they get results from qualitative tests more quickly, it doesn’t seem to be the case.

We also compared the analytical sensitivities of the two types of tests.  The qualitative test that we used had a claimed detection limit of 25 IU/L.  That is, a sample with an hCG concentration above 25 IU/L should produce a positive result.  Of the samples that gave a positive result, about 20% had an hCG concentration that was <25 IU/L which indicated that the qualitative test was more analytically sensitive than we expected it to be.  In my opinion, that’s a good thing.

Because we determined the actual pregnancy status of all the patients with a positive result, we were also able to determine how well the qualitative and quantitative tests performed at determining pregnancy status.  Both tests did quite well and showed high sensitivity and specificity.  That is, there were very few false-negative or false-positive results.  From a clinical perspective, a false-negative result is more concerning than a false-positive one because a pregnant patient who is incorrectly identified as not being pregnant risks being exposed to a medical intervention that could harm the fetus.  The false-negative rate was lowest, only 0.1%, when the qualitative test was evaluated against pregnancy status and the detection threshold of 25 IU/L.  The performance of the quantitative serum hCG test was identical.  So, both the qualitative and quantitative serum hCG tests do a very good job at ruling-out a possible pregnancy.

So, given this evidence, I would conclude that while qualitative hCG tests could be replaced by quantitative tests, there is really no compelling reason to do so.

Is it time to abandon the hCG discriminatory zone?

I've written about ectopic pregnancy a few times now (see this and this).  The use of hCG testing in the evaluation of a woman with a suspected ectopic pregnancy is invaluable.  For many years doctors have relied upon the concept of a "discriminatory zone."  That is, an hCG concentration above which an intrauterine pregnancy should always be visible using transvaginal ultrasound.  The hCG concentration that is often used as the discriminatory zone is between 1,000 and 2,000 IU/L.  If no fetus is seen then the woman may receive treatment for a presumed ectopic pregnancy.

Early recognition and treatment of an ectopic pregnancy is critical because it is a leading cause of maternal death in the first trimester.  Ectopic pregnancies are terminated by the use of the drug methotrexate or surgery.  Methotrexate is a folic acid antagonist and a powerful teratogen that causes malformations in a developing fetus.  The use of methotrexate has increased substantially in the last few years because it has fewer risks and is less expensive than surgery.  However, methotrexate is sometimes given to women with an erroneous diagnosis of ectopic pregnancy which results in the loss of a viable pregnancy or the delivery of infants with birth defects.

Two recent reports have shown a spotlight on this problem:

• The first study reported the outcomes of 8 pregnancies that were incorrectly diagnosed as ectopic and in whom the mother was treated with methotrexate.  Sadly and unsurprisingly, all 8 pregnancies had terrible outcomes.  Two pregnancies resulted in severely malformed infants.  One was liveborn at 37 weeks and had Tetralogy of Fallot, pulmonary atresia, congenital scoliosis, 7 ribs on left side and 11 ribs on right side, and a single kidney.  The other was stillborn at 30 weeks and had Tetralogy of Fallot, horseshoe kidney, and a single umbilical artery.  The other 6 pregnancies were aborted, 3 spontaneously and 3 deliberately.
• The second study addressed the reliability of the hCG discriminatory zone by evaluting 202 patients that met the following criteria: 1) a transvaginal sonogram showing no intrauterine pregnancy; 2) an hCG test performed on the same day as the ultrasound; 3) documentation of a subsequent viable intrauterine pregnancy.  80% had an hCG concentration less than 1,000 IU/L (well below the discriminatory zone), in 9% it was between 1,000 and 1,499 IU/L, in 6% it was between 1,500 and 1,999 IU/L, and in 5% it was 2,000 IU/L or greater (above the discriminatory zone).  The highest hCG concentration observed was 6,567 IU/L.

While the idea of an hCG discriminatory zone is an appealing one, it is clearly not something that can be relied on to make an important therapeutic decision.  The authors of the second study (above) concluded exactly that and recommend using follow-up sonography and serial hCG testing in hemodynamically stable patients before treating for presumed ectopic pregnancy.

FDA and FTC Crack Down on hCG Diet Products

Although the hCG diet is slightly outside of the realm of The Pregnancy Lab, we have discussed it in the past because we get questions about it all the time. Don't even consider doing this diet to shed your extra holiday pounds. On December 6, 2011, the FDA and Federal Trade Commission issued warnings to a number of companies ordering them to stop selling their homeopathic hCG products.  The warning letter states that, it is unlawful to "advertise that a product can prevent, treat, or cure human disease unless you possess competent and reliable scientific evidence". In addition, the FDA says a 500-calorie diet by itself is pretty risky. You can get gallstones and develop other health problems from such severe restrictions on what you eat.

If you are considering this or any diet a good resource is an article by American Dietetic Association.

Ectopic pregnancy and the hCG discriminatory zone

I’ve written about the use of hCG testing in the evaluation of patients with suspected ectopic pregnancies.  As a reminder, the diagnostic tests used in the work-up of a woman with symptoms of an ectopic pregnancy include a combination of transvaginal ultrasound and the laboratory measurement of serum hCG concentrations.

Transvaginal ultrasound is used to visualize the fluid-filled, gestational sac in which the embryo is growing. Ultrasound may reveal 1) a normal, intrauterine pregnancy, 2) an ectopic pregnancy, or 3) neither. The latter finding would be considered an indeterminate result and occurs in about 10-30% of women being evaluated for ectopic pregnancy. An indeterminate result could represent early intrauterine pregnancy, ectopic pregnancy, or fetal loss.

These indeterminate results are often interpreted against the hCG “discriminatory zone,” the concentration of serum hCG above which a gestational sac in the uterus should be readily observed. The discriminatory zone is often considered to be between 1,500 and 3,000 IU/L.

A recent study investigated how well a serum hCG concentration ≥3,000 IU/L worked to differentiate an ectopic pregnancy from a normal pregnancy in women with symptoms of ectopic pregnancy but with indeterminate ultrasound findings. What they reported was quite interesting.

There were 141 women with an indeterminate ultrasound result and 57 of these had an hCG concentration ≥3,000 IU/L. Of these, 82% actually did have intrauterine pregnancies even though their hCG concentrations were above the discriminatory zone.

There is a very important methodological consideration to consider in this study. Pelvic rather than transvaginal ultrasonography was used and emergency department physicians and not radiologists performed it. The study purposely used pelvic ultrasound because its use in an emergency department allows for the rapid and accurate detection of an intrauterine pregnancy in the majority of cases. It also can result in a shorter stay for the patient, which, presumably, would result in lower costs. In this same study, 99% of 115 women with an intrauterine pregnancy were identified as having one using pelvic ultrasound.

The main conclusion of this study is that in women with an indeterminate pelvic ultrasound, the use of an hCG discriminatory zone does not provide information to help differentiate ectopic from intrauterine pregnancy.

The hCG Diet: Don't waste your money

It's almost predictable.  Each time I give a talk about the biochemistry of hCG and clinical uses of hCG tests, I get asked a question about the hCG diet.  A comment on a recent post on this blog also asked about its safety and effectiveness.  I decided that even though the topic is slightly outside of the realm of The Pregnancy Lab, it should be addressed here.

First some history.   In 1954, Dr. Albert T. W. Simeons, a British physician, first proposed the use of low-dose hCG injections (125 IU/day) combined with a very reduced calorie diet (500 calories/day) as a way to promote extreme weight loss.  He described his method in a manuscript titled "Pounds & Inches: A New Approach to Obesity." He believed that during pregnancy hCG promotes the mobilization and consumption of excessive fat deposits for the benefit of the developing fetus.

Several clinical studies that examined the effectiveness of the hCG diet have been performed over the years.  Tthe majority of these have clearly shown that there is no merit or truth to the claims that the hCG diet works.  While many individuals in these studies have, indeed, lost weight, there was no difference in weight loss between those who used hCG and those who used a placebo.  A meta-analysis published in 1995 concluded that the hCG diet "does not bring about weight loss or fat redistribution, nor does it reduce hunger or induce a feeling of well-being."

Many people who have tried the hCG diet will swear by it and I have no doubt that many of them have actually lost weight.  However, the weight loss is due to the ultra-low calorie diet and not to the use of hCG.  The FDA was warned consumers that hCG weight-loss products are fraudulent.

Notably, many hCG products are labeled as being "homeopathic."  Homeopathy is  a form of alternative medicine in which practitioners treat patients using highly diluted medicines.  As such, these types of hCG preparations contain undectable quantities of the hormone.  The use of this type of preparation is the equivalent to using nothing at all.  Note the "100% Hormone-Free" labeling of the hCG drops in the image above and recall that hCG is, itself, a hormone.

Perhaps most importantly, the safety of the hCG diet has recently been called into question.  Daily injections of 200 IU of hCG can be used to extend the egg maturation phase of the female menstrual cycle suggesting that the actual use of hCG for weight loss could have reproductive effects.  Prostate cells express receptors for hCG raising the concern, in men, that hCG use could lead to an enlarged prostate gland and even prostate cancer.

The lack of demonstrable weight loss effects and the possible safety concerns should be enough to make most people think twice before trying the hCG diet.  With any luck, the fad will fade away again soon.  This time, let's hope it is for good.

Four reasons for a positive hCG test in the absence of pregnancy

“Why is the pregnancy test positive if she’s not pregnant?”

This is a question I’ve been asked several times and it’s a good one.  The query usually comes from a nurse, doctor, or other healthcare provider after performing a test for human chorionic gonadotropin (hCG) and getting a positive or elevated result that they did not anticipate.

Because hCG is a hormone normally produced during pregnancy, hCG tests are used to diagnose the pregnant patient.  That makes it easy to think of hCG tests as “pregnancy tests.”  While that’s not an inaccurate label for them, identifying hCG tests as pregnancy tests gives the impression that is all they are supposed to do.  Technically, hCG tests are designed to qualitatively detect and/or measure the hormone in urine or blood and there are other reasons besides being pregnant that can cause hCG to be present.

I can think of four different reasons why hCG could be present in a non-pregnant woman.

1. Biochemical pregnancy.  A biochemical pregnancy occurs when a woman becomes pregnant yet has a spontaneous loss of the fetus before she even knew she was pregnant.  If hCG testing occurs before all of the hCG has been metabolized out of the body then hCG can be detected by a lab test.  This situation is not as uncommon as one might think for two reasons.  First, hCG tests are frequently performed in healthcare settings in order to identify the pregnant patient in order to avoid any medical interventions that are potentially harmful to a fetus.  Second, hCG tests are capable of detecting very low concentrations of the hormone.  The high frequency of testing combined with the analytical sensitivity of the tests means that biochemical pregnancies are easily detected.
2. Pituitary hCG.  Although the placenta normally produces hCG during pregnancy, it can be made by the pituitary gland.  The pituitary gland is a small structure in the brain that secretes many different hormones that function to regulate many endocrine organ systems.  Interestingly, three hormones normally produced by the pituitary gland (thyroid stimulating hormone, follicle stimulating hormone, and luteinizing hormone) are structurally similar to hCG.  Pituitary hCG is more commonly detected in women greater than 55 years of age but can be detected in women as young as 41 years.  Non-pregnant women with pituitary hCG usually have low concentrations of hCG present in the blood and urine.  Importantly, concentrations of hCG produced by the pituitary gland don’t show the rapid increases that occur during pregnancy.
3. Malignancy.  Cancer cells sometimes make hCG.  While many different types of cancer have been shown to make the hormone, it’s most commonly associated with the gestational trophoblastic diseases and certain types of germ cell tumors of the testes.  Because testicular tumors occur only in men, the question of detecting hCG in the absence of pregnancy is clearly not relevant.
4. Interfering antibodies.  Some women have antibodies in their blood that can interfere with hCG tests and cause a positive or elevated result in the absence of hCG.  Only hCG tests performed on blood can be affected by this problem because the interfering antibody molecules aren’t normally present in the urine.  This can be a serious problem because some women have been mistakenly diagnosed with cancer due to the false-positive hCG test result and have undergone unnecessary treatments for it.  The frequency of this problem is difficult to know but it’s probably very low.  Over the last several years, the manufacturers of hCG tests have worked to minimize possible interference from these antibodies but nothing can be done to completely eliminate the problem.  When alerted, the laboratory can help to determine if an hCG test result is falsely positive due to this issue.

So, just because an hCG test result is interpreted as positive doesn’t automatically mean that a woman is pregnant.  There are very valid reasons for detecting hCG in the absence of pregnancy.  That said, when the hCG test result doesn’t match the clinical picture, the laboratory should still be asked that question!  When alerted to the discrepancy, the lab can help to investigate the problem and perhaps shed some light on the cause.

There is quite a bit more to say on each of those four causes but I’ll save those comments for future posts.

 

Wanted: a rapid pregnancy test using whole blood

Most laboratorians would agree that when it comes to hCG testing for pregnancy status, a blood sample is preferred over a urine sample.  Why is that?

• Following implantation of a fertilized egg, hCG is first detected in the blood.  hCG in the urine usually appears a day or two later.
• Blood-based hCG test results provide a concentration of the hormone whereas urine tests are qualitative (positive or negative)
• In early pregnancy, when hCG concentrations are still relatively low, a negative result can be obtained from a dilute urine sample (i.e. a false-negative result).

An earlier post presented the pros and cons of the different types of pregnancy tests. To summarize here: qualitative (yes/no) tests are typically easier to perform and, if urine is the sample being tested, then qualitative tests can truly be performed at the point-of-care.  If a blood sample is used, it has to be centrifuged to separate the liquid part of the blood (serum) from the solid part (blood cells), a step that is nearly always performed in the laboratory.  As such, qualitative hCG tests using a blood sample cannot be performed at the point-of-care.

A recent study challenges that idea.

Blood samples were collected from 632 women (aged 18-51 years) presenting to an emergency room. These blood sample were tested for hCG in two ways: 1) traditional, quantitative serum hCG testing in the laboratory and 2) qualitative, point-of-care hCG testing in the emergency room using the whole blood sample instead of serum.  Note that the qualitative test used was not designed nor approved by the FDA for use with whole blood and that the test results were interpreted after 10 minutes whereas the test instructions required result interpretation after 5 minutes.

When compared to the results of the quantitative test performed in the lab, the qualitative test performed on whole blood (instead of serum) performed quite well.  100% of the laboratory-negative results were interpreted as negative using the qualitative test and 96% of the laboratory-positive results were interpreted as positive using the qualitative test.  The hCG concentration of the 4% of "false-negative" results (9 out of 216) ranged from 5 to 50 IU/L.  Notably, the hCG detection threshold of the qualitative test is identified as 25 IU/L.

So, what does all this mean?  Well, the authors of the study suggest that it can be difficult to obtain urine samples from some patients which makes testing hCG in blood more attractive.  But because blood-based hCG tests are normally always performed in the laboratory, waiting for the lab results can waste time.  Hence, the appeal of testing whole blood for hCG at the point-of-care.  The results of this limited study suggest that, perhaps, whole blood hCG testing using devices that were designed for urine or serum, has merit.

What the study did not address, however, are the (often) complicated state and federal rules that regulate lab testing.  The study's use of a qualitative hCG test using whole blood instead of serum is problematic.  Changing the type of sample recommended by the test manufacturer is a thorny issue for laboratorians who are ultimately responsible for all lab tests performed.  It is typically the lab's responsibility to determine if an alternate sample type can be used for a given laboratory test and this type of substitution, however appealing, cannot be widely adopted without a thorough evaluation and validation by the laboratory.

Intriguing?  Yes.  Easily implemented?  Not quite.

Surprising details about the most sensitive urine pregnancy tests

Here’s a multiple-choice question to consider:

Which type of qualitative urine hCG test devices (a.k.a pregnancy tests) are capable of detecting the lowest concentrations of hCG?

A. The devices that can be purchased at a local pharmacy for use at home (over-the-counter (OTC) tests).

B. The devices used in hospitals, clinics, and doctor’s offices (point-of-care (POC) tests).

C. Both types of devices are equivalent.

The correct answer is A.

Surprised? I was too. Logic suggests that the urine hCG tests that are frequently used in healthcare settings (versus home use) would probably do best at detecting the hormone at lower concentrations.

There have been two studies that have investigated the analytical sensitivities of urine hCG tests. One study used samples prepared by adding hCG to male urine to achieve hCG concentrations of 6.3, 13, 25, and 50 IU/L. Fifteen different OTC pregnancy tests were evaluated, twelve of which claimed an hCG detection limit of 50-100 IU/L (the other three claimed 25 or 40 IU/L). All but one of the fifteen devices produced positive results at an hCG concentration of 25 IU/L. Curiously, the one device that did not claimed a detection limit of 25 IU/L.

The other study (disclaimer: I was one of the investigators) used urine samples obtained from pregnant women within 10 days of their expected period. In my opinion, this is the optimal type of sample to use because pregnancy urine contains a mixture of different hCG variants and not just a single form of the hormone. That is important because not all pregnancy tests detect the same variants of the hormone equally and that, in turn, can influence device sensitivity. These urine samples were diluted to low hCG concentrations and then tested with both OTC and POC pregnancy tests. While all the devices claimed an hCG detection limit of 25 IU/L, we observed that they were capable of detecting hCG at much lower concentrations. The POC devices were sometimes four times more sensitive than claimed and the OTC devices were sometimes sixteen times more sensitive!

The greater analytical sensitivity of the pregnancy test devices appeared to be a function of the urine sample used. For example, using the hCG Combo device, urine samples from five different women produced positive results at 25 IU/L, while samples from two women produced positive results at a lower concentration (6 and 13 IU/L) and samples from three women produced positive results at a higher concentration (50 IU/L). Likewise, the OTC devices also showed variability in analytical sensitivity with urine samples obtained from different women although all of them produced positive results at hCG concentrations below the claimed 25 IU/L detection limit. In other words, the OTC pregnancy tests gave positive results at lower hCG concentrations than did the POC pregnancy tests!

We suspect that home pregnancy tests have greater analytical sensitivity than their POC counterparts because of differences in the amount of urine the devices require. OTC devices absorb urine from the urine stream during voiding and, as such, they use a much larger volume of urine than the tests used in healthcare settings (approximately 5-10 times more).

To be certain, the physician who orders a urine hCG test on a patient has the same desire as the woman who performs her own urine test at home: they both want to know about pregnancy status. In the former scenario, the test is often being done to rule-out a possible pregnancy prior to a medical intervention that could harm a fetus. In the latter, the test is being done to satisfy a curiosity. Which test do you think should be the most sensitive?

hCG and the thyroid gland

First things first. The main job of human chorionic gonadotropin (hCG) hormone is to increase the synthesis of progesterone in early pregnancy. Without steadily increasing concentrations of progesterone, an early pregnancy will fail. hCG usually has nothing to do with the thyroid gland.

As a reminder, the thyroid gland, located in the neck in close proximity to the larynx (voice box), is basically responsible for controlling our body's metabolism. It is regulated by a different hormone: thyroid stimulating hormone or TSH.

So hCG maintains pregnancy and TSH regulates the thyroid gland. Sometimes, however, hCG can act like TSH and crank up the function of the thyroid gland. When the thyroid gland is in an over-active state the condition is called hyperthyroidism. Symptoms of hyperthyroidism include weight loss, increased appetite, heat intolerance, hair loss, weakness and fatigue, irritability, and sweating. In extreme cases, hear palpitations, and shortness of breath can occur. How can hCG cause hyperthyroidism? The answer lies in the molecular structure of these two hormones.

As it turns out, hCG and TSH are rather similar to each other. Both are composed of two different protein subunits. One of those protein subunits is called "alpha" and the other "beta." The alpha subunits of hCG and TSH are identical but the beta subunits are a different; but not by much. The beta subunits of hCG and TSH are about 40 percent identical. When present a very high concentrations, hCG can actually stimulate the thyroid gland sending it a message to go into over-drive. In other words, hCG can sometimes act like TSH. Fortunately, this doesn't happen unless the amount of hCG in the blood gets to be very, very elevated.

How elevated? Well, that has been the subject of some recent investigations. Conventional wisdom was that hyperthyroidism could occur in women with an hCG concentration that was greater than 50,000 IU/L. While this hCG concentration may seem very elevated, it's actually quite normal in pregnant women who are in their first trimester. Because the vast majority of pregnant women in early pregnancy do not have symptoms of hyperthyroidism, the 50,000 IU/L threshold didn't seem accurate.

In one study (disclaimer: I participated in that study), an hCG threshold of 400,ooo IU/L was identified as the concentration above which actual symptoms of hyperthyroidism could occur. The lower hCG concentration of 200,000 IU/L was identified as the threshold above which a majority of women demonstrated biochemical signs of hyperthyroidism (i.e. decreased TSH) but they did not have actual symptoms of hyperthyroidism until the hCG increased to twice that amount.

Another study reported that women developed suppressed TSH and/or symptoms of hyperthyroidism only when the hCG concentration was greater than 100,000 IU/L.

A normal, singleton, intrauterine pregnancy doesn't usually produce such sustained elevations of hCG. This means that the vast majority of pregnant women will never have symptoms of hCG-induced hyperthyroidism. However, extreme elevations of hCG can be produced in women with gestational trophoblastic disease (GTD). These are a family of diseases that arise from an abnormal fertilization event so hCG is produced even in the absence of a viable fetus.

The bottom line is that extremely high hCG concentrations can cause biochemial and physical signs of hyperthyroidism but these are rarely the result of the hCG concentrations found in normal pregnancy.