Introduction
Hypercholesterolemia is common in medical practice, but not all cases are equal. Some individuals may have a transient spike in cholesterol due to dietary indiscretions or a secondary cause. In contrast, others may carry a genetic predisposition, leading to persistently high levels from a young age. Familial Hypercholesterolemia (FH), a genetic disorder, is a prime example of the latter, causing significantly elevated cholesterol levels that can result in premature cardiovascular diseases.
Yet, the differentiation between FH and a simple case of severe hyperlipidemia isn’t always straightforward. Subtle clinical findings, a detailed family history, and even advanced genetic testing might be necessary to tease apart the two. The following case highlights this diagnostic dilemma, presenting the story of a man with significantly elevated cholesterol levels. By showcasing this case, we aim to underscore the importance of a thorough approach to hypercholesterolemia.
Despite the concerning family history, he reported no chest pain or breathlessness, either at rest or during physical activity. He wasn’t on any medications, held a desk job, and was the father of a young family, which included two children.
A Young man With Severe Hypercholesterolemia?
A 38-year-old man presents for a routine blood test as he is planning to apply for life insurance. He is a non-smoker and exercises regularly. He has no other risk factors for coronary artery disease, including diabetes or hypertension. Yet, his family history revealed a different story. His 65-year-old father underwent Coronary Artery Bypass Graft (CABG) surgery when he was just 45. Further, two of his paternal uncles suffered myocardial infarctions in their 40s, with one incident proving fatal.
Despite the concerning family history, he reported no chest pain or breathlessness, either at rest or during physical activity. He wasn’t on any medications, held a desk job, and was the father of a young family, which included two children.
Initial Blood Test Results
He had his blood test. Most of the results, including Thyroid, Renal and Liver function, were normal. However, his lipid profile was surprisingly abnormal, with an LDL-Cholesterol of 10.1 mmol/L (390 mg/dl), as shown in Fig-1.
Given these abnormal results, one immediate question should arise: Is this Familial Hypercholesterolemia (FH) or simply a case of severe hyperlipidemia?
Stepwise Approach to Hypercholesterolemia
There are five main steps when we come across such high cholesterol levels:
- Repeat and Confirm: It’s essential to verify hypercholesterolemia. The patient should have at least two fasting LDL levels checked. For added confidence, consider sending the tests to different labs.
- Review prior lab tests: Don’t overlook the importance of historical data. Revisiting previous results, potentially going back to childhood, can provide valuable insights. If past results, or even a handful of them, showed normal LDL-C levels, then secondary causes of hypercholesterolemia might be more probable than familial hypercholesterolemia.
- Detailed Family History: A thorough family history can illuminate the probability of familial hypercholesterolemia. Inquiring about premature coronary events or procedures in all first and second-degree relatives is vital. Probing about interventions like bypass surgery, angioplasty, or instances of sudden cardiac death in family members can provide more clarity.
- Physical signs: Observable cholesterol deposits can hint at familial hypercholesterolemia. Look for signs like Arcus Cornealis, Xanthelasma, and Xanthomas. Notably, Achilles tendon xanthoma is a strong indicator of FH.
- Utilise FH calculator: Employ tools like the Dutch Lipid Score calculator to assess the likelihood of familial hypercholesterolemia being present.
Our Case: Upon retesting his lipid profile in a different lab, the LDL-C was confirmed at an alarmingly high 10.5 mmol/L (406 mg/dL). Unfortunately, we didn’t have access to his past results for comparison. The detailed family history, as previously mentioned, already suggested a genetic predisposition. On physical examination, the Arcus Cornealis was evident, though there were no signs of Xanthomas or Xanthelasma. His calculated Dutch Lipid Score was alarmingly high at 16, solidly placing him in the “definite FH” category.
Based on the cumulative score, calculated via a dedicated FH calculator, individuals are classified into the following categories:
-  Score 1-2  →  Unlikely FH
- Score 3-5  →  Possible FH
- Score 6-8  →  Probable FH
- Score >8   →  Definite FH
Genetic Testing for FH
Following the initial evaluation and raised suspicion for Familial Hypercholesterolemia (FH), he opted for genetic testing, for which he qualified based on multiple criteria, including his significant Dutch Lipid Clinical Network (DLCN) score and elevated LDL-cholesterol levels. Four primary genes are currently tested for FH: LDLR, PCSK9, APOB, and LDLRAP1. However, about 95% of mutations in individuals with heterozygous FH are found in the LDLR gene, also known as the LDL receptor gene.
Indeed, a mutation was identified in his LDLR gene, conclusively diagnosing him with Heterozygous Familial Hypercholesterolemia (He-FH) (Fig-2).
It’s crucial to understand that even if this patient’s genetic test returns negative, we would still manage him as a case of Familial Hypercholesterolemia. Approximately 10-20% of individuals displaying the clinical features of FH may receive a negative genetic test. This discrepancy can be attributed to unidentified mutations or the polygenic nature of their hypercholesterolemia.
Lipoprotein(a) or Lp(a) measurement
To further assess his risk of cardiovascular disease, beyond familial hypercholesterolemia, we measured his Lp(a) which was severely elevated at 132 mg/dl (Fig-3). Lp(a) is an independent risk factor for coronary artery disease, vascular conditions, and aortic valve anomalies, irrespective of LDL-cholesterol levels. Levels exceeding 30 mg/dl are deemed elevated, while anything over 50 mg/dl is considered significantly so.
Now, our young patient who approached us for a straightforward blood test, has genetically proven familial hypercholesterolemia and a very high Lp(a). These two factors, place him at the highest risk for developing premature coronary artery and vascular diseases.
Functional Assessment (Stress Test)
Given his heightened risk and significant family history, a stress echocardiogram was performed. He exercised on the treadmill for 10 minutes without experiencing angina, but his stress ECG indicated ischemia(Fig-4 & 5). Subsequent invasive coronary angiography revealed extensive coronary artery disease affecting all arteries, including the left main. Based on these findings, he opted for coronary artery bypass surgery.
Management of Risk Factors
Now that he has undergone coronary artery revascularization, the primary focus shifts to optimizing risk factors and promoting a health-conscious lifestyle, which includes adhering to a balanced diet and engaging in regular exercise. His primary concern remains hypercholesterolemia.
For lipid management, our objective for him is to achieve an LDL-C level below 1.4 mmol/L. We prescribed Rosuvastatin 40 mg and Ezetimibe 10 mg daily to meet this goal. After initiating this regimen, there was a marked improvement in his lipid profile (Fig-6) compared to his initial results. However, his LDL is still at 3.6 mmol/L (139 mg/dl) and not at the desired level.
A few months later, he underwent another blood test. This time, his liver enzymes had escalated to over three times the normal limit (Fig-8). Consequently, the Rosuvastatin dose was decreased to 20 mg.
Following the adjustment in his statin dosage, his liver enzymes returned to normal. However, his LDL levels increased once more, reaching 5.1 mmol/L (197 mg/dl).
Now, we’re faced with a high-risk patient who, after CABG, has an LDL level exceeding 6 mmol/L while on 20 mg Rosuvastatin and 10 mg Ezetimibe daily. This situation is far from ideal. If these elevated levels persist, especially in conjunction with his already high Lp(a), it’s just a matter of time before his grafts fail.
It’s at this juncture that we must explore alternative treatment methods for hypercholesterolemia, such as PCSK9 inhibitors. This category includes monoclonal antibodies like Evolocumab, as well as PCSK9 synthesis inhibitors like Inclisiran.
PCSK9 Inhibitor
He began receiving monthly injections of Evolocumab, while maintaining his Rosuvastatin dose at 20 mg/d and Ezetimibe at 10 mg/d. A few months into this regimen, his LDL had significantly reduced to 1.5 mmol/L (Fig-9).
Family Screening for Familial Hypercholesterolemia (FH)
Another crucial component of a Familial Hypercholesterolemia diagnosis is the recommendation for “cascade screening”. This involves testing first and second-degree family members, but only for the specific gene mutation identified in the diagnosed patient. Our patient, with two young children aged 6 and 13, faced this directly. Post-discussion and realizing the 13-year-old exhibited high LDL-Cholesterol levels, a decision was made to test him for the LDLR gene mutation. The results came back positive. Recognizing the potential implications of the FH diagnosis for his future health, they made the informed decision to initiate statin therapy for him and to emphasize a healthy lifestyle from this early age onwards.
The family was counselled on the importance of regular check-ups to monitor the efficacy of the treatment. They were also made aware of potential psychological impacts, especially for the younger members coming to terms with a genetic diagnosis.
Conclusion
Our patient’s journey, from a seemingly routine blood test to a diagnosis of Familial Hypercholesterolemia, underscores the complexities of the approach to Hypercholesterolemia. Familial Hypercholesterolemia is not just a diagnosis on paper; it’s a call to action, requiring vigilance and prompt intervention to prevent serious cardiovascular events. Even when genetic tests prove inconclusive, the clinical presentation, familial patterns, and other phenotypic features remain paramount in guiding our diagnostic and therapeutic approaches.
This case serves as a reminder for clinicians to look beyond numbers. Every cholesterol level tells a story, and in cases like these, it might be whispering tales of generations affected and the urgency to intervene.
Thank you for the informative article. I am 25 and been diagnosed with FH at 20. I have a healthy lifestyle and exercise regularly. I did a stress test with my cardiologist which he said was excellent. I am on excellent therapy and my LDL is 60 md/dl. My question is that do I need a calcium score to see how my arteries are?
Thank you, Nasim. Given your current situation, a coronary calcium score is not necessary. This test is primarily used to assess the risk for future coronary artery disease. However, since you’ve already been diagnosed with Familial Hypercholesterolemia, you’re inherently at a higher risk. It is reassuring that you had an “excellent” stress test. This especially means that a coronary calcium score test is unlikely to alter your management plan. If it was low or zero, there is a chance that it could miss serious underlying disease such as this case, or if score was high, it may result in unnecessary and even harmful procedures. My advice would be to continue maintaining your healthy lifestyle, staying committed to regular exercise and medications, and closely following your cardiologist’s recommendations.
Hi, Thank you for presenting such interesting and educations case of FH. I have a question and appreciate your insight. Is genetic testing required to start a patient on a PCSK9 inhibitor, or would a high Dutch Lipid Score be enough?
No, genetic testing is not mandatory. For this patient, a DLCN score above 6 is sufficient to qualify him. However, they must first be treated with maximally tolerated statins AND ezetimibe. If the LDL remains above 1.8 mmol/l (70 mg/dl), or if they experience side effects (such as abnormal LFT, as seen in this patient), then they would be eligible for PCSK9 inhibitors or Inclisiran.
By the way, 10-20% of patients with FH have a negative genetic test, so the phenotype is extremely important.