Introduction
Xanthoma are deposits of lipid in tissue that are important clinical sign of systemic disease such as lipid metabolism disorder, particularly can be seen in severe hypertriglyceridemia (³1000 mg/dl) (1,2). Disorder of lipid metabolism or dyslipidemia divide into two categories, primary and secondary. Primary disorder occurs when alteration of genetic defects that directly affect lipoprotein. Secondary disorder occurs when other disorder alters lipoprotein metabolism indirectly. Often disorder of lipid metabolism results from combination of primary and secondary causes, as diabetes mellitus (DM) occurs in a person who has an inherited defect in lipoprotein metabolism (3,4).
Herein, a case presents a 30-year-old male patient came with multiple papules and nodules xanthoma in both hands and legs caused hand contracture, further investigation revealed that he had very severe hypertriglyceridemia and DM. Comprehensive management is needed to improve his problem and prevent other serious complication such as cardiovascular disease.
Case Presentation
30-year-old man has multiple lesions for a year. The lesions were progressively increasing size and number widespread over both hands and legs that caused hand contracture. There was no other complaint he had admitted. There was no past medical history. Alcohol consumption, smoking, hypertension, family history included diabetes mellitus, lipid disorder, and other metabolic disorder were denied. The physical examination revealed multiple yellow-brown papulonodular lesions in both hands and legs that some were coalesce one another. The lesions in his hand was known as xanthoma. Body mass index was 25.1 kg/m2, classified into overweight. A lipid profile examination revealed high triglyceride (TG) levels 7060 mg/dl, hypercholesterolemia 630 mg/dL, low HDL-C (high density lipoprotein cholesterol) 22 mg/dL, and high LDL-C (low density lipoprotein cholesterol) 110 mg/dL. Other laboratory abnormalities revealed high random blood glucose 370 mg/dL and high haemoglobin A1C (HbA1c) 11.2%. DNA analysis for any receptor gene mutation was not done due to its high cost. In conclusion, he had dyslipidaemia in domination of TG levels (very severe hypertriglyceridemia) and DM. The patient started on 145 mg fenofibrate as monotherapy. The patient also started 20 iu detemir insulin in the morning and 14 iu aspart insulin before meals. After two months consumed fenofibrate his TG levels 4380 mg/dL, cholesterol level 455 mg/dL, LDL-C 32.9 mg/dL, and HDL-C 23 mg/dL, fasting plasma glucose (FPG) 157 mg/dL, and 2-hour post prandial plasma glucose (2-h PPG) 239 mg/dL. As target TG level in this patient could not be achieved with monotherapy, combination with other lipid-lowering agent considered. He started to take 20 mg atorvastatin and added insulin dose gradually. After two month used combination of fenofibrate and statin, his TG level was 3275 mg/dL, cholesterol level 427 mg/dL, LDL-C 25.8 mg/dL, and HDL-C 23 mg/dL. Still combination of statin and fenofibrate had not been achieved the target, another lipid-lowering agent was added, 10 mg of ezetimibe. Lipid profile performed after he consumed combination of three drugs for a month, TG level 2984 mg/dl, cholesterol level 327 mg/dL, LDL-C 20 mg/dL, and HDL-C 24 mg/dL. However decreasing of cholesterol and triglyceride level was following by improvement of xanthomas.
Discussion
According to the World Health Organization (WHO), the prevalence of dyslipidemia in 2008 was 37% in men and 40% in woman that considered to cause mortality and morbidity (5).
Dyslipidemia is lipid metabolism disorder caused by either increased or decreased of plasma lipid. It is caused by increased of cholesterol, LDL-C or triglyceride, and decreased of HDL-C. Diagnosis of dyslipidemia based on laboratory of lipid plasma. For the measurement of triglyceride and LDL-C levels, patient must fast at least 12 hours before blood sampling (6). The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) classifies serum triglyceride levels into four categories: normal, <150 mg/dl; borderline high, 150–199 mg/dl; high, 200–499 mg/dl; and very high, ³500 mg/dl. NCEP ATP III also classifies serum cholesterol into three categories: desirable, <200 mg/dl; borderline high, 200-239 mg/dl; and high, ³240 mg/dl. HDL-c classifies into two categories: low, <40; and high > 60 (7). According to endocrine society clinical practice guideline, they modified the NCEP ATP III triglyceride classification to involve additional classification of severe hypertriglyceridemia, 1000-1999 mg/dl and very severe hypertriglyceridemia when TG levels reach ³2000 mg/dL (8).
Very high lipid plasma level can be caused by primary, secondary lipid metabolism disorder, or a combination of both (3,4,9). Despite familial aetiology of lipid metabolism disorder, either primary or secondary cause cerebrovascular disease as long term effect of uncontrolled lipid plasma level (10).
In our case, Patient came with multiple yellow-brown papulonodular lesions in both hands and legs that some were coalesce one another lead to hand contracture. Lipid plasma levels of this patient show he had very severe hypertriglyceridemia 7060 mg/dl, hypercholesterolemia 630 mg/dl, low HDL-C 22 mg/dL, and high LDL-C 110 mg/dL. He also had just diagnosed with DM according to his random blood glucose and HbA1C, 370 mg/dl and 11.2% respectively.
Recommendation based on ADA (American Diabetes Association) 2020, lipid management in diabetes include lifestyle therapy, optimize glycemic control for patients with elevated triglyceride levels and /or low HDL, statin, and other lipoprotein therapy. It is advised that diabetes patients aged 20-39 years with additional atherosclerotic cardiovascular disease risk factors to initiate statin therapy in addition to lifestyle therapy. It is reasonable to use high intensity statin therapy in patients with diabetes at higher risk. In very high risk patient, if LDL-C ³ 70 mg/dL on maximally tolerated statin dose, consider adding additional LDL-lowering therapy (such as ezetimibe or PCSK9 inhibitor). ADA also said that statin and fibrate combination therapy has not been shown to improve atherosclerotic disease outcomes and increase risk for transaminase levels, myositis, and rhabdomyolysis (9). Whereas according to ESC/EAS (European Society of Cardiology) 2019, if dominated by high TG levels, a fibrate often a combination of a statin and a fibrate may be needed (10).
In this patient initiated a daily dose of fenofibrate 145 mg, 20 iu detemir insulin in the morning and 14 iu aspart insulin before meals, after two months his TG level 4380 mg/dL, total cholesterol level 455 mg/dL, LDL-C 32.9 mg/dL, and HDL-C 23 mg/dL, FPG 157 mg/dL, and 2-h PPG 239 mg/dL. As target TG level in this patient could not be achieved with monotherapy, combination with other lipid-lowering agent considered. He started to take 20 mg of atorvastatin and added insulin dose gradually, after two month used combination of fenofibrate and statin with close monitoring transaminase levels and sign of myositis and rhabdomyolysis, his TG level was 3275 mg/dL, cholesterol level 427 mg/dL, LDL-C 25.8 mg/dL, and HDL-C 23 mg/dL. Still combination of statin and fenofibrate had not been achieved the target, so another lipid-lowering agent was given, 10 mg of ezetimibe. Lipid profile performed after he consumed combination of three drugs for a month, TG level decreased into 2984 mg/dl, cholesterol level decreased into 327 mg/dL, LDL-C 20 mg/dL, and HDL-C 24 mg/dL. By decreasing lipid profile, this patient has an improvement of his xanthomas.
Summary
The importance of recognizing xanthomas that may has underlying disorder. This case provide very severe hypertriglyceridemia with xanthoma as first clinical presentation that result in hand contracture. In this case, very severe hypertriglyceridemia exacerbated by diabetes mellitus. Delaying treatment can lead to other serious complications.