MANAGEMENT OF PATIENT WITH FAMILIAL COMBINED HYPERLIPOPROTEINEMIA: A CASE STUDY

Familial combined hyperlipoproteinemia is considered one of the most common genetic hyperlipidemias in the general population with estimated prevalence 0.5 %–2.0 % of all inherited dyslipidemias. This disorder frequently coexists with other metabolic diseases such as obesity, insulin resistance, hypertension, nonalcoholic fatty liver disease. Association of hyperlipoproteinemia and type 2 diabetes mellitus can be explained due to the fact, that familial combined hyperlipoproteinemia is caused by genetic variability, including genes encoding the upstream transcription factor 1. The last regulates nearly 40 genes implicated in lipid, lipoprotein and carbohydrate metabolism, as well as immune response. Polymorphism in the upstream transcription factor 1 is strongly associated with dyslipidemia, impaired glucose tolerance, insulin resistance, and type 2 diabetes mellitus. In this report on example of clinical case we want to pay attention of practitioners to the problem of familial causes of hyperlipidemias, which leads to early onset of atherosclerosis, cardiovascular disease, and, finally, to premature disability of the affected person. Because of the frequent overlapping with the features of metabolic syndrome, this serious disorder is often not recognized and treated timely. Our patient was a 43 year old male, who was referred to the clinic with complaints of angina pain and dyspnoea provoked by minimal physical exertion, palpitations, irregular heartbeats, lower extremities and face oedema. At the age of thirty in the patient have developed type 2 diabetes mellitus, during last 7 years it was insulin dependent, the course was severe, glycaemia was poorly controlled by the therapy. Also he had essential hypertension III grade. At the age of 37 years the patient suffered from ST-elevated myocardial infarction, one year later occurred recurrent myocardial infarction. His family history was strongly positive for atherosclerosis and cardiovascular disease, as well as type 2 diabetes mellitus. In laboratory testing the fasting blood sample revealed a grossly lipemic serum, with total cholesterol level 17.75 mmol/L, very low density lipoproteins 3.41 mmol/L, low density lipoproteins 13.64 mmol/L, high density lipoproteins 0.7 mmol/L. Diagnosis: «Familial combined hyperlipoproteinemia (Fredrickson type 2B). Acute coronary syndrome: Unstable angina IIB. Postinfarction (STEMI 2014, 2015) cardiosclerosis. Essential hypertension III degree III stage. Heart failure with left ventricular systolic and diastolic dysfunction, EF 36 %. III functional class NYHA. Stage D AHA. Risk score 4 (very high).Type 2 diabetes mellitus, insulin dependent, severe course. Non-alcoholic fatty liver, 2 degree. Nodular goitre I degree, euthyroid state» was established. Management of this patient includes lifestyle modification and combined lipid lowering therapy in high doses: rosuvastatin and choline fenofibrate. Unfortunately, in this case target levels of cholesterol and triglycerides were not achieved: minimal level of total cholesterol was 12.29 mmol/L, and level of triglycerides was 41.48 mmol/L. Risk estimates based on risk charts, scores, or functions used in the general population, probably grossly underestimate the real risk of this patient with familial combined hyperlipoproteinemia. Coexistence of extremely high level of cholesterol and type 2 diabetes mellitus significantly aggravates and advances each other's course, comparing with the isolated disorders.

Familial combined hyperlipoproteinemia (FCHL) is very frequent and is one of the most common genetic hyperlipidaemias in the general population with estimated prevalence 0.5 %-2.0 % of all inherited dyslipidaemias, being the most common in patients affected by CAD (10 %) and among acute myocardial infarction (MI) survivors aged less than 60 years (11.3 %). This percentage increases to 40 % when all the MI survivors are considered without age limits [2]. However, because of the peculiar variability of laboratory parameters and lack of diagnostic criteria, this serious disease is often remains undiagnosed and untreated.
FCHL is characterized by: a) increase in cholesterolemia and/or triglyceridemia in at least two members of the same family; b) intraindividual and interfamilial variability of the lipid phenotype; c) increased risk of premature CAD [3]. As recent studies have shown, FCHL is an oligogenic disorder with variable penetrance [4]. Frequently it coexists with other metabolic diseases such as obesity, insulin resistance (IR), type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFL), and hypertension [5]. Consistent susceptibility loci have beenmapped to chromosomes 1q21-23, 11p14.1-q12.1, and 16q22-24.1 [6]. An association of FCHL with the region in chromosome 1q21-1q23 [7,8] has been reported. This region includes several genes which might contribute to FCHL phenotype, including the upstream transcription factor 1 gene (USF1) [7]. USF1 encodes a transcription factor, which regulates nearly 40 genes implicated in lipid, lipoprotein and carbohydrate metabolism, as well as immune response [4]. As reported Putt et al. (2004), polymorphism in USF1 is strongly associated with impaired glucose tolerance, IR, and T2DM.
Herein we discuss the clinical case of FCHL, a highly atherogenic disorder that evidently led to premature disability and to early mortality of the patient.

CASE REPORT
A 43 year old male complained of retrosternal squeezing, burning pain, radiated to the left arm and left part of the neck, provoked by minimal physical activity (e.g. household chores), sometimes at rest, required nitroglycerine intake (up to 7 td), diminished effect of nitro-glycerine, dyspnoea, provoked by walking ground level up to 100 m, palpitations, irregular heartbeats, lower extremities and face oedema.
From history of the presenting disease it is known that in this patient about 10 years occur blood pressure elevations (max 180/120 mm Hg, usual 130/90 mm Hg). At the age of 37 years the patient suffered from ST elevated MI (STEMI) of left the ventricular (LV) inferior wall, one year later recurrent STEMI of the LV anterior wall, septum, and apex occurred. It was recommended an angiography, percutaneous intervention with implantation of drug-eluting coronary stent; due to economic reasons, the patient had refused this procedure. Regular (3-4 times per year) receive in-patient treatment with some positive dynamics. However, despite regular out-patient medication intake, the therapy effect is not lasting. The current hospitalization associated with deterioration that occurred during last month: dyspnoea was progressed, angina pain developed more often, physical tolerance decreased, effect of nitro-glycerine diminished.
At the age of 30 years it was diagnosed T2DM, during last 7 years it is insulin dependent. The oral hypoglycaemic therapy was switched to insulin due to myocardial infarction. Course of the disease is severe, compensation is not achieved, fasting plasma glucose is within 13-17 mmol/L. Also during last year the patient suffered from diabetic foot and community acquired pneumonia in lower lobe of right lung. For diabetic foot he received conservative treatment with improvement. Pneumonia had a protracted course.
The patient denies alcohol consumption. During last 4 years the patient does not smoke, but before he had smoked 2 packs per day during 20 years (equals 40 pack-years).
His family history include: early death of relatives in paternal line, proband's father suffered from MI at the age of 44, and T2DM; he died at the age of 62.
During physical examination it was noticed that patient look older, than the passport age and was slightly depressive. He was well oriented to space and time. The patient's posture was active. It was revealed central type of obesity (BMI 35.8 kg/m², waist circumference 146 cm, waist to hip ratio 1.23). Multiple eruptive xanthomas were detected on the skin of the trunk and extremities. Visible changes of the neck shape were not detected, but during thyroid palpation in the left lobe was revealed a node ≈1 cm Ø. In the lungs to auscultation occurred bronchial breathing, diminished on basal parts. Peripheral pulses were regular and weak. Apex beat was in 5 th intercostal space 2 cm to the left of the left midclavicular line, 3 cm², weak. Heart auscultation detected soft S1 on the apex and loud A2 sounds to auscultation, diffuse systolic murmur (grade II) at all points was revealed. Abdomen was increased in size due to subcutaneous fat, participated in breathing actively; during palpation was soft and nontender. Hepatomegaly (+3 cm) was revealed, liver was soft and nontender to palpation. Spleen was not palpated. Oedema of the lower half of shins and foots occurred. Stool and diuresis were not changed.
Blood tests revealed: hyperglycaemia 16.6 mmol/L, elevated HBA1c up to 11.9 %. Fasting blood sample revealed a grossly lipemic serum: total cholesterol 17.75 mmol/L, very low density lipoproteins 3.41 mmol/L, low density lipoproteins 13.64 mmol/L, high density lipoproteins 0.7 mmol/L, triglycerides 71.35 mmol/L. Liver, kidney, and thyroid function tests fell into normal ranges. It should be noted, that all blood tests were standardized, because the serum was chyle and usual estimation could not be performed.
Urine analysis detected glucose 170 mmol/L and traces of protein.
Instrumental methods of examination displayed the following changes. ECG revealed postinfarction cardiosclerosis of the LV anterior and posterior wall, apex. Transthoracic echocardiography demonstrated dilation of all heart chambers, hypertrophy of the LV, and its posterior wall hyperkinesia, decreased contractility, EF 36 %, apical aneurism, diastolic dysfunction of the LV 2 degree, and signs of pulmonary hypertension 3 degree. Thyroid ultrasound showed diffuse nodular goitre, left lobe node 8.3 mm Ø. Abdominal ultrasound detected moderate hepatomegaly, steatohepatosis, increased echogenicity of pancreas. Chest X-ray revealed signs of venous congestion, initial basal pneumofibrosis of both lungs.
Based on findings mentioned above, final diagnosis was established: Main Evidence and recommendations regarding management of specific risk factors in this group of patients are insufficient and call for the development of intervention-based evaluations, aiming at describing the role and magnitude of these treatments and their impact on lipid profile and metabolic burden.
Management of this patient includes lifestyle modification and medication. It was recommended for this patient to avoid smoking and alcohol intake, to lower body weight, and diet with reduced saturated and animal fats, simple sugars, sodium (less 6 g per day). Medication include bisoprolol 5 mg od, ramipril 5 mg od, rosuvastatin 40 mg od, choline fenofibrate 135 mg, aspirin 75 mg od, clopidogrel 75 mg od, toracemide 5 mg od, insulin human NPH 20 IU 2 td 8-00, 20-00, insulin human 10 IU 3 td before meal.
Therapy choices differ depending on the type of mixed hyperlipidaemia a patient has. However, fibrates are usually needed in addition to statins. Statin-induced myopathy is more likely in patients who are also taking fibrates, so careful monitoring of side effects is important.
Unfortunately, despite the lipid lowering treatment, in this case target levels of cholesterol and triglycerides were not achieved: Minimal level of total cholesterol was 12.29 mmol/L, and triglycerides were 41.48 mmol/L. Prognosis for this patient is unfavourable. Ischemic heart disease and T2DM have developed in young age, the course of disease is progressive, symptoms are poorly controlled.
Risk estimates based on risk charts, scores, or functions used in the general population, grossly underestimate the real risk in this patient with FCH. Coexistence of extremely high level of cholesterol and T2DM significantly aggravates and advance each other's course, comparing with the isolated disorders.