Main Menu

Case details

Two sisters, aged 19 & 17 years, were referred to the dermatologist because they had large number of yellowish spots on the exposed parts of the body.

On thorough examination and after conducting a series of laboratory investigations they were advised to increase physical activity and reduce the intake of fats

What is the cause of yellow spots?

How are the medical advices going to help these patients?

Case Discussion

Both the sisters are having xanthomas, Xanthomas are lesions characterized by accumulation of lipid-laden macrophages. Xanthomas can develop in the setting of altered systemic lipid metabolism or as a result of local cell dysfunction. Most of the disorders of hyperlipidemia (Hyperlipoproteinemia) are associated with xanthomas.

Altered Lipoprotein metabolism (Hyperlipoproteinemia)


Lipids are insoluble in water; therefore, they are transported as complexes of lipoproteins with specific apoproteins. These proteins also serve as ligands to specific receptors, they facilitate transmembrane transport, and they regulate enzymatic activities. Lipoproteins may be classified according to their density, chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Lipoproteins may also be separated by electrophoresis into beta (LDL), prebeta (VLDL), Broad beta (IDL)and alpha (HDL) lipoproteins.

Metabolism of lipoproteins

The metabolic pathways of lipoproteins can be divided into exogenous and endogenous pathways. The exogenous lipoprotein pathway refers to the metabolism of intestinal lipoproteins, the triglyceride-rich chylomicrons, primarily formed in response to dietary fat.

The endogenous lipoprotein pathway refers to lipoproteins and apoproteins that are synthesized in tissues other than the intestines, predominantly in the liver. The liver secretes the triglyceride-rich VLDL that contains apoproteins B-100, C-II, and E into the circulation.

In the peripheral tissues, particularly adipose and muscle tissue, VLDL is cleaved by lipoprotein lipase (LPL), extracting most of the triglycerides and forming an IDL that contains apoproteins B-100 and E. IDL can be taken up by the liver through the LDL receptor, or it can be converted to the cholesterol-rich LDL that contains apoprotein B-100. LDL is removed from the circulation primarily by the liver through the LDL receptor.


Chylomicrons are similarly metabolized and are converted to chylomicron remnants after the action of lipoprotein lipase , which are internalized through remnant receptors (Apo E receptors) in to the liver.

The main role of HDL is to accept cholesterol and to transport it back to the liver (reverse cholesterol transport).

Lipoprotein (a) (Lp[a]) consists of an LDL-like particle with apoprotein B and a side chain of a highly glycosylated protein. Lp(a) has a role not only in atherogenesis but also in thrombogenesis because of its homology with plasminogen.


Hyperlipoproteinemia is a metabolic disorder characterized by abnormally elevated concentrations of specific lipoprotein particles in the plasma. Hyperlipidemia (ie, elevated plasma cholesterol or triglyceride levels or both) is present in all hyperlipoproteinemia.

Hyperlipoproteinemia may be primary or secondary

Alterations in lipoproteins result either from genetic mutations that yield defective Apo lipoproteins (primary hyperlipoproteinemia) or from some other underlying systemic disorder, such as diabetes mellitus, hypothyroidism, or nephrotic syndrome (secondary hyperlipoproteinemia). The biochemical and genetic basis for the inherited disorders of lipid and lipoprotein metabolism differ considerably.

Primary Hyperlipoproteinemia

Traditionally, hyperlipidemia have been classified according to 5 phenotypes described by Fredrickson. These phenotypes are based on the Electrophoretic patterns of lipoprotein level elevations that occur in patients with hyperlipoproteinemia.

1) Type I hyperlipidemia

Familial lipoprotein lipase deficiency is an example of a primary disorder in which a deficiency of lipoprotein lipase in tissue leads to a type I pattern of hyperlipidemia, with a massive accumulation of chylomicrons in the plasma. This effect results in a severe elevation of plasma triglyceride levels. Plasma cholesterol levels are not usually elevated. Patients with type I may present in early childhood, often with acute pancreatitis. Eruptive xanthomas are the most characteristic skin manifestation of this disorder.(See figure below)

2) Type II hyperlipidemia

Cholesterol is bound to Apo lipoprotein B-100 as LDL in interstitial fluid. Cells may acquire cholesterol via an LDL receptor on the cell membrane. Familial LDL receptor deficiency and familial defective apoprotein B-100 are examples of primary defects that can lead to the accumulation of LDL, which corresponds to a type IIa pattern of hyperlipidemia. Plasma cholesterol levels are severely elevated, but plasma triglyceride levels are typically normal. Patients with type IIa have severe atherosclerosis and may present with tendinous or tuberous xanthomas as well as Xanthelasmas.(See figure below)

The type IIb pattern is characterized by the accumulation of both LDL and VLDL, with variable elevations of both triglyceride levels and cholesterol levels in the plasma. This is probably due to abnormal apo B protein.Patients with type IIb may present as adults with tendinous or tuberous xanthomas as well as Xanthelasmas.

3) Type III hyperlipidemia(Familial dysbetalipoproteinemia)

Type III hyperlipidemia is characterized by the accumulation of IDL, which is manifested by increases in both triglyceride levels and cholesterol levels in the plasma. A genetic basis for the primary disorder, familial dysbetalipoproteinemia, has been well established. Various mutations of apoprotein E impair its ability to bind to the IDL receptor. Patients with type III present as adults with premature atherosclerosis and xanthomas, particularly plane (palmar) xanthomas.(See figure below)

4) Type IV hyperlipidemia (Familial hypertriglyceridemia)

Familial hypertriglyceridemia is an example of a primary defect resulting in type IV hyperlipidemia.  there is over production of VLDL.Accumulation of VLDL causes severe elevations of plasma triglyceride levels. Plasma cholesterol levels are typically normal. A definitive molecular defect has not been established. Patients with type IV may present with eruptive xanthomas . This type of pattern is commonly associated with coronary heart disease, type II diabetes mellitus, obesity, alcoholism, and administration of progestational hormones.

5) Type V

Genetic defects of the apolipoprotein C-II gene result in the accumulation of chylomicrons and VLDL, which is the type V pattern of hyperlipidemia. Patients with this type have severe elevations of triglyceride levels in the plasma. These patients, like those with lipoprotein lipase deficiency, may present in early childhood with acute pancreatitis and eruptive xanthomas.

Other types of hyperlipoproteinemia

6) Decreased synthesis of HDL due to decreased formation of apoprotein A-I and apoprotein C-III leads to decreased reversed cholesterol transport, resulting in increased LDL levels, premature coronary artery disease, and plane xanthomas.

7) Hepatic lipase deficiency

Deficiency of the enzyme leads to accumulation of large triacylglycerol-rich HDL and VLDL remnants. Patients have xanthomas and coronary heart disease

Secondary Hyperlipidemia

Hyperlipidemia is also related to a variety of secondary causes. 

Secondary hypercholesterolemia can be found in pregnancy, hypothyroidism, cholestasis, and acute intermittent porphyria. 

Secondary hypertriglyceridemia can be associated with oral contraceptive use, diabetes mellitus, alcoholism, pancreatitis, gout, sepsis due to gram-negative bacterial organisms, and type I glycogen storage disease. 

Combined hypercholesterolemia and hypertriglyceridemia can be found in nephrotic syndrome, chronic renal failure, and steroid immunosuppressive therapy.


Clinical manifestations

Cutaneous xanthomas associated with hyperlipidemia can be clinically subdivided into following types-


  • Xanthelasma palpebrarum is the most common of the xanthomas. The lesions are asymptomatic and usually bilateral and symmetric. The lesions are soft, velvety, yellow, flat, polygonal papules around the eyelids. Xanthelasma may be associated with hyperlipidemia. When associated with hyperlipidemia, any type of primary hyperlipoproteinemia can be present. Some secondary hyperlipoproteinemia, such as cholestasis, may also be associated with xanthelasmas.










Figure- showing Xanthelasma palpebrum


  • Tuberous xanthomas are firm, painless, red-yellow nodules. Tuberous xanthomas usually develop in pressure areas, such as the extensor surfaces of the knees, the elbows, and the buttocks. Tuberous xanthomas are particularly associated with hypercholesterolemia and increased levels of LDL. They can be associated with familial dysbetalipoproteinemia and familial hypercholesterolemia, and they may be present in some of the secondary hyperlipidemia (e.g., nephrotic syndrome, hypothyroidism).












Figure -showing Tuberous xanthomas


  • Tendinous xanthomas appear as slowly enlarging subcutaneous nodules related to the tendons or the ligaments. The most common locations are the extensor tendons of the hands, the feet, and the Achilles tendons. The lesions are often related to trauma. Tendinous xanthomas are associated with severe hypercholesterolemia and elevated LDL levels, particularly in the type IIa form. They can also be associated with some of the secondary hyperlipidemias, such as cholestasis.












Figure- showing tendinous xanthomas


  • Eruptive xanthomas most commonly arise over the buttocks, the shoulders, and the extensor surfaces of the extremities. The lesions typically erupt as crops of small, red-yellow papules on an erythematous base, and they may spontaneously resolve over weeks. Eruptive xanthomas are associated with hypertriglyceridemia, particularly that associated with types I, IV, and V (high concentrations of VLDL and chylomicrons). They may also appear in secondary hyperlipidemias, particularly in diabetes.











Figure showing eruptive xanthomas


  • Plane xanthomas can occur in any site. Involvement of the palmar creases is characteristic of type III dysbetalipoproteinemia. They can also be associated with secondary hyperlipidemia, especially in cholestasis. Generalized plane xanthomas can cover large areas of the face, the neck, and the thorax.











Figure showing plane xanthomas


Laboratory Investigations of hyper lipoproteinemia

  • Measurement of plasma lipid and lipoprotein levels while the patient is on a regular diet after an overnight fast of 12-16 hours. Abnormal lipoprotein patterns can often be identified after determining serum cholesterol and triglyceride levels and visual inspection of the plasma sample (stored at 4°C).
  • In some cases, performing electrophoresis and ultracentrifugation of whole plasma specimens may be necessary to help establish a diagnosis.
  • Appropriate blood, urine, and radiographic workups are required to rule out a secondary cause of hyperlipidemia. Lipoprotein profiles are primarily used to assess cardiac risk and to aid in the diagnosis of lipid metabolism disorders.


Treatment of the hyperlipidemia initially consists of diet and lipid-lowering agents such as statins, fibrates, bile acid–binding resins, probucol, or nicotinic acid. Xanthomas are not always associated with underlying hyperlipidemia, but when they are, diagnosing and treating underlying lipid disorders is necessary to decrease the size of the xanthomas and to prevent the risks of atherosclerosis.

Eruptive xanthomas usually resolve within weeks of initiating systemic treatment and tuberous xanthomas usually resolve after months, but tendinous xanthomas take years to resolve or may persist indefinitely.


Supportive care

  • Weight reduction and a diet low in saturated fat and cholesterol are advocated.
  • Patients should avoid alcohol and estrogen in certain types of hyperlipoproteinemia.

Prognosis- Prognosis is good if the underlying cause is treated.



Please help "Biochemistry for Medics" by CLICKING ON THE ADVERTISEMENTS above!

One Response to Case study- Xanthomas with hyperlipidemia

  • Dear students,
    We have already covered metabolism of lipoproteins and hyperlipidemia in the class.
    A few details were left due to shortage of time. Pay attention, these are important clinically also.