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Mönckeberg's arteriosclerosis, or Mönckeberg's sclerosis, is a non-inflammatory form of
arteriosclerosis Arteriosclerosis, literally meaning "hardening of the arteries", is an umbrella term for a vascular disorder characterized by abnormal thickening, hardening, and loss of elasticity of the walls of arteries; this process gradually restricts th ...
(
artery An artery () is a blood vessel in humans and most other animals that takes oxygenated blood away from the heart in the systemic circulation to one or more parts of the body. Exceptions that carry deoxygenated blood are the pulmonary arteries in ...
hardening), which differs from
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
traditionally. Calcium deposits are found in the muscular middle layer of the walls of arteries (the
tunica media The tunica media (Neo-Latin "middle coat"), or media for short, is the middle tunica (layer) of an artery or vein. It lies between the internal elastic lamina of the tunica intima on the inside and the tunica externa on the outside. Artery The ...
) with no obstruction of the lumen. It is an example of
dystrophic calcification Dystrophic calcification (DC) is the calcification occurring in degenerated or necrotic tissue, as in hyalinized scars, degenerated foci in leiomyomas, and caseous nodules. This occurs as a reaction to tissue damage, including as a consequenc ...
. This condition occurs as an age-related degenerative process. However, it can occur in pseudoxanthoma elasticum and idiopathic arterial calcification of infancy as a pathological condition, as well. Its clinical significance and cause are not well understood and its relationship to
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
and other forms of vascular
calcification Calcification is the accumulation of calcium salts in a body tissue. It normally occurs in the formation of bone, but calcium can be deposited abnormally in soft tissue,Miller, J. D. Cardiovascular calcification: Orbicular origins. ''Nature M ...
are the subject of disagreement. Mönckeberg's arteriosclerosis is named after Johann Georg Mönckeberg, who first described it in 1903. The severity of calcium deposits formed by Mönckeberg's arteriosclerosis can be categorized into stages based on the histological appearance. Understanding these stages can help to understand disease progression and how the disease is caused. Stage 1 involves the formation of calcium deposits both inside and outside the vascular smooth muscle cells which compose the tunica media. Calcification outside of the vascular smooth muscle cells are commonly associated with damage to
elastic fiber Elastic fibers (or yellow fibers) are an essential component of the extracellular matrix composed of bundles of proteins (elastin) which are produced by a number of different cell types including fibroblasts, endothelial, smooth muscle, and ai ...
s in the extra-cellular matrix. These calcium deposits also develop on the
internal elastic lamina The internal elastic lamina or internal elastic lamella is a layer of elastic tissue that forms the outermost part of the tunica intima of blood vessels. It separates tunica intima from tunica media. Histology It is readily visualized with light ...
. Stage 2 and Stage 3 involve the formation of calcified sheaths spanning an increased diameter through the tunica media. Stage 4 then involves the formation of bony tissue from these calcifications through the process of osseous metaplasia.


Pathophysiology

The exact pathophysiology of Monckeberg's arteriosclerosis remains uncertain. However, it is thought that the condition arises from the fatty degeneration of
smooth muscle Smooth muscle is one of the three major types of vertebrate muscle tissue, the others being skeletal and cardiac muscle. It can also be found in invertebrates and is controlled by the autonomic nervous system. It is non- striated, so-called bec ...
cells within the arterial media, leading to the formation of a mass that undergoe
hyaline degeneration
and eventually
calcification Calcification is the accumulation of calcium salts in a body tissue. It normally occurs in the formation of bone, but calcium can be deposited abnormally in soft tissue,Miller, J. D. Cardiovascular calcification: Orbicular origins. ''Nature M ...
. Typically, this results in minimal clinical impact due to the small reduction in the arterial lumen. However, if
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
also occurs, the clinical symptoms become more pronounced and severe. Monckeberg's calcification typically occurs near the
internal elastic lamina The internal elastic lamina or internal elastic lamella is a layer of elastic tissue that forms the outermost part of the tunica intima of blood vessels. It separates tunica intima from tunica media. Histology It is readily visualized with light ...
or, less frequently, in the media of muscular arteries without alterations in calcium metabolism. Its clinical importance is not yet fully understood. Some recent studies suggest a connection between Monckeberg's calcification and metabolic vascular calcification. However, another study, which examined 143 histologically normal femoral arteries from young, healthy multi-organ donors, suggests otherwise. This study found that 25% of participants, with a mean age of 38 years (ranging from 14 to 59 years), had Monckeberg's calcification without any cardiovascular disease risk factors. This indicates that Monckeberg's calcification may develop early in life, potentially due to abnormal osteogenic differentiation o
vascular progenitor cells


Signs and symptoms

Typically, Mönckeberg's arteriosclerosis is not associated with symptoms unless complicated by
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
, calciphylaxis, or accompanied by some other disease. However, the presence of Mönckeberg's arteriosclerosis is associated with poorer prognosis. This is probably due to vascular calcification causing increased arterial stiffness, increased
pulse pressure Pulse pressure is the difference between systolic and diastolic blood pressure. It is measured in millimeters of mercury (mmHg). It represents the force that the heart generates each time it contracts. Healthy pulse pressure is around 40  ...
and resulting in exaggerated damage to the
heart The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...
and
kidneys In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and right in the retro ...
. The clinical symptoms of Mönckeberg's arteriosclerosis are similar to
giant cell arteritis Giant cell arteritis (GCA), also called temporal arteritis, is an inflammatory autoimmune disease of large blood vessels. Symptoms may include headache, pain over the temples, flu-like symptoms, double vision, and difficulty opening the mout ...
in which the two can be mistakenly interchanged. A temporal artery biopsy (TAB) can be performed to differentiate between the two disease states. As the disease progresses, the arteriosclerosis results in the obstruction of normal blood flow, and potentially the formation of blood clots. This can result in changes in blood pressure, and depending on the severity of the calcification organ
ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...
. In rare instances, headaches and facial pain have also been reported by patients with Mönckeberg's arteriosclerosis. Mönckeberg's arteriosclerosis may also be a risk factor for the development of cranial
infarction Infarction is tissue death (necrosis) due to Ischemia, inadequate blood supply to the affected area. It may be caused by Thrombosis, artery blockages, rupture, mechanical compression, or vasoconstriction. The resulting lesion is referred to as a ...
s. Intercranial Mönckeberg's arteriosclerosis has been commonly found in people with malignant tumors who died of cerebral infarctions. In cranial
autopsies An autopsy (also referred to as post-mortem examination, obduction, necropsy, or autopsia cadaverum) is a surgical procedure that consists of a thorough examination of a corpse by dissection to determine the cause, mode, and manner of death; ...
, areas of Mönckeberg's arteriosclerosis were located near the sites of infarction. Mönckeberg's arteriosclerosis has little or no impact on the risk o
microvascular surgery
Mönckeberg's arteriosclerosis is typically an incidental finding, detected through clinical examination or plain radiography, and may be associated with
diabetes mellitus Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained hyperglycemia, high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or th ...
or
chronic kidney disease Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...
. The condition is characterized by calcification of the
tunica media The tunica media (Neo-Latin "middle coat"), or media for short, is the middle tunica (layer) of an artery or vein. It lies between the internal elastic lamina of the tunica intima on the inside and the tunica externa on the outside. Artery The ...
, leading to hardened, pulseless vessels that often still provide normal distal perfusion, unlike atherosclerosis where the tunica intima is affected and the vessel lumen diameter is compromised. Despite its prevalence being less than 1% of the population, Mönckeberg’s arteriosclerosis generally does not adversely affect the outcome of microvascular surgery, as evidenced by successful free flap reconstructions using these vessels with minimal impact on flap survival.


Cause

Minor degrees of calcification of the cardiovascular system are common in elderly people, usually individuals over 50 years old, and the prevalence of vascular calcification is increased by some diseases (see Epidemiology section). Vascular calcification results from the deposition of calcium phosphate crystals (
hydroxyapatite Hydroxyapatite (International Mineralogical Association, IMA name: hydroxylapatite) (Hap, HAp, or HA) is a naturally occurring mineral form of calcium apatite with the Chemical formula, formula , often written to denote that the Crystal struc ...
) as a consequence of disordered calcium phosphate regulation in the blood vessel. Hydroxyapatite is secreted in vesicles that bleb out from vascular smooth muscle cells or pericytes in the arterial wall. The mechanism of vascular calcification is not fully understood, but probably involves a phenotypic change in the vascular smooth muscle cells in the wall with activation of bone-forming programs. Numerous regulators of calcification such as
osteopontin Osteopontin (OPN), also known as bone /sialoprotein I (BSP-1 or BNSP), early T-lymphocyte activation (ETA-1), secreted phosphoprotein 1 (SPP1), 2ar and Rickettsia resistance (Ric), is a protein that in humans is encoded by the ''SPP1'' gene (sec ...
,
osteoprotegerin Osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor (OCIF) or tumour necrosis factor receptor superfamily member 11B (TNFRSF11B), is a cytokine receptor of the tumour necrosis factor (TNF) receptor superfamily encoded by th ...
, matrix gla protein and fetuin-A, receptor activator of NF-kappa-B, receptor activator of NF-kappa-B ligand and
tumor necrosis factor Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
(TNF)-related apoptosis-inducing ligand protein have been implicated in this process. In addition, elevated inorganic phosphate may have direct signaling effects which can induce the progression of Mönckeberg's arteriosclerosis. Elevated inorganic phosphate (a result of phosphorus imbalance) induces intercellular signaling mechanisms in the smooth muscle, which can both induce smooth muscle cell apoptosis and medial calcification. This mechanism could help to further describe the relationship between
uremia Uremia is the condition of having high levels of urea in the blood. Urea is one of the primary components of urine. It can be defined as an excess in the blood of amino acid and protein metabolism end products, such as urea and creatinine, which ...
, such as in patients with ESRD, and development of Mönckeberg's arteriosclerosis. It is unclear whether Mönckeberg's arteriosclerosis is a distinct entity or forms part of a spectrum of vascular calcification that includes atherosclerosis and calcification in the inner layer of the artery wall (
tunica intima The tunica intima (Neo-Latin "inner coat"), or intima for short, is the innermost tunica (biology), tunica (layer) of an artery or vein. It is made up of one layer of endothelium, endothelial cells (and macrophages in areas of disturbed blood flo ...
), calcification of the internal elastic lamina, calcification of cardiac valves and widespread soft tissue calcification. The existence of Mönckeberg's arteriosclerosis has been disputed and it has been proposed that it is a part of a continuum of atherosclerotic disease: the majority of atherosclerotic plaques contain some calcium deposits and calcification of the internal elastic lamina is common in pathological specimens labelled as Mönckeberg's arteriosclerosis. However, studies in animals suggest that there is mainly a medial pattern of vascular calcification reflects different underlying mechanisms of disease, and despite involvement of the internal elastic lamina, evidence of
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
is rare in Mönckeberg's arteriosclerosis.


Diagnosis

Diagnosis of this rare disease is often misdiagnosed or delayed, leading to results such as amputation and death. In a rare case, an 80 year old woman displayed symptoms resembling temporal arteritis. However, pathological findings confirmed that it was Mönckeberg's arteriosclerosis instead. Due to this, it is important to utilize comprehensive medical testing, examination, and diagnostic tests. Often Mönckeberg's arteriosclerosis is discovered as an incidental finding in an
X-ray An X-ray (also known in many languages as Röntgen radiation) is a form of high-energy electromagnetic radiation with a wavelength shorter than those of ultraviolet rays and longer than those of gamma rays. Roughly, X-rays have a wavelength ran ...
radiograph Radiography is an imaging technique using X-rays, gamma rays, or similar ionizing radiation and non-ionizing radiation to view the internal form of an object. Applications of radiography include medical ("diagnostic" radiography and "therapeu ...
, on
mammogram Mammography (also called mastography; DICOM modality: MG) is the process of using low-energy X-rays (usually around 30 kVp) to examine the human breast for diagnosis and screening. The goal of mammography is the early detection of breast cancer ...
s, in
autopsy An autopsy (also referred to as post-mortem examination, obduction, necropsy, or autopsia cadaverum) is a surgical procedure that consists of a thorough examination of a corpse by dissection to determine the cause, mode, and manner of deat ...
, or in association with investigation of some other disease, such as
diabetes mellitus Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained hyperglycemia, high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or th ...
or
chronic kidney disease Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...
. The diagnosis is usually confirmed by a radiography result or an ultrasonography. Typically calcification is observed in the arteries of the upper and lower limb although it has been seen in numerous other medium size arteries. In the radial or ulnar arteries it can cause "pipestem" arteries, which present as a bounding pulse at the end of the calcific zone. It may also result in "pulselessness." Epidemiological studies have used the ratio of ankle to brachial blood pressure ( ankle brachial pressure index, ABPI or ABI) as an indicator of arterial calcification with ABPI >1.3 to >1.5 being used as a diagnostic criterion depending on the study. However this type of non-invasive diagnostic tool could lead to falsely elevated values, especially individuals with diabetes that have lower limb ischemia. In an observational study, 11% of patients that met the criteria of diabetes and critical ischemia had exhibited false ABI levels. It was found that the calcification of the arteries could potentially cause misuse of the sphygmomanometer since the calcified arteries would make it more difficult to compress.


Management and prevention


Guidelines and recent studies

Currently, there are no guideline therapies established to treat Mönckeberg's arteriosclerosis. There have been more studies as of recently to learn more about the disease and potential pharmacological managements. Recent studies that are showing potential emerging therapies that can help treat arteriosclerosis. A therapy using vasostatin-1, which is a chromogranin A derived peptide, has shown potential in helping treat Mönckeberg's arteriosclerosis. There are still further discussions and trials needed to help define treatment goals for Mönckeberg's arteriosclerosis.


Medications

There are some recommendations for the clinical treatment for people who have complications related to Mönckeberg's arteriosclerosis. Specifically for people with underlying phosphate disorders, the use of phosphate binders, low-dose vitamin D, calcimimetics, magnesium,
bisphosphonate Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed to treat osteoporosis. Evidence shows that they reduce the risk of fracture in ...
s, sodium thiosulfate, and aldosterone antagonists have been proposed. Lowering calcium and phosphate levels in people with calciphylaxis, along with increasing
hemodialysis Hemodialysis, American and British English spelling differences#ae and oe, also spelled haemodialysis, or simply ''"'dialysis'"'', is a process of filtering the blood of a person whose kidneys are not working normally. This type of Kidney dialys ...
and treating potential ischemic necrosis is also recommended.


Prevention

Since Mönckeberg's arteriosclerosis is more commonly associated with individuals that have diabetes mellitus and chronic kidney disease, prevention methods can be associated with those disease states. The most fundamental therapeutic goal in prevention would be to lower an individuals risk of cardiovascular events. This can be done by eliminating or controlling risk factors such as smoking or tobacco use,
obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...
, lack of physical activity,
diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
,
hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...
, chronic kidney disease, chronic inflammatory conditions, systemic
lupus erythematosus is a collection of autoimmune diseases in which the human immune system becomes hyperactive and attacks healthy tissues. Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, ...
, and
hypercholesterolemia Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia (high levels of lipids in the blood), hyperlipoproteinemia (high levels of lipoproteins in the blood), ...
. Since Mönckeberg's arteriosclerosis is not well understood more research is needed to further understandings of how this disease state comes about and treatment methods for it. Some promising studies have been exploring this concept and have created 3D printed tubular structures similar to the human body's own vasculature to use as a model for testing.


Clinical Studies and Case Reports


28-Year-Old male

A 28-year-old male in Saudi Arabia presented with swelling in both of his thighs, despite no past medical history significant of chronic illness, trauma, or surgeries. The individual noted significant pain due to the swelling and reported difficulty walking. As a result of this, the individual was subjected to physical examination, hematological investigations, and a variety of imaging such as a doppler examination, radiograph and MRI. This testing uncovered calcified arteries and a collection of soft tissue near the femoral arteries and veins, which lead to a disruption in the right femoral artery. Extensive analysis of the individual's condition lead medical professionals to the conclusion that Mönckeberg's arteriosclerosis was suspected as the cause for their symptoms. The individual was treated with antibiotics, bed rest, ice packs, as well as anticoagulation therapy. They also received an interventional surgery to help remove the excess fluid from their thighs. After subsequent follow-up, the individual's ability to walk was restored and imaging of their arterial calcification had improved.


62- Year-Old male

A 62-year-old diabetic male presented with angina that had lasted for six days until coming in for a coronary angiography when it was noticed they had signs of Mönckeberg's arteriosclerosis. It was noticed when performing the coronary angiography the attempts to do the radial puncture were unsuccessful. All routine labs of the individual were at normal levels but it was noticed that the patient may have recently experienced a myocardial infarction. The individual was found to have their left anterior descending artery to experience 95% calcification of the artery. A percutaneous angioplasty with drug stents were done to potentially help with the occlusion found. The individual was also given statins and anti-platelet therapy to help treat the condition as well. Since the drug stents were placed, the individual has been under monitoring with follow-up visits and has not experienced any peripheral ischemia.


75-Year-Old male

A 75-year-old South Asian male presents with complaints of an unilateral headache and overall head and facial pain, with specific pain centered on the left side of their neck. The individual had first noticed the pain about two weeks before their visit to the clinic. The pain was described to be ongoing and continuous throughout the day and rated 6-7 on the numerical visual analog scale (VAS). They reported no relieving factors and multiple different associated factors including scalp tenderness and non-specific shoulder pain. The individual had tried multiple pain medications medications ranging from over-the-counter medications (OTC) to prescription medications including
pregabalin Pregabalin, sold under the brand name Lyrica among others, is an anticonvulsant, analgesic, and anxiolytic amino acid medication used to treat epilepsy, neuropathic pain, fibromyalgia, restless legs syndrome, opioid withdrawal, generalized anx ...
and
indomethacin Indometacin, also known as indomethacin, is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as a prescription medication to reduce fever, pain, stiffness, and swelling from inflammation. It works by inhibiting the production of pr ...
but had reported to receive no pain relief from any of the medications they had taken. An orofacial pain evaluation was performed which resulted in no abnormalities found in the patient. The individual had their pain, which was produced by Mönckeberg medial arteriosclerosis, controlled by using high dosed
corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invo ...
s combined with the usage of warm compresses and transcutaneous electrical nerve stimulation (TENS).


69-Year-Old Female

A case report describes a 69-year-old female with Monckeberg’s arteriosclerosis affecting her uterine vessels, following long-term endometritis and experiencing premature menopause.


In an elderly patient

Mönckeberg medial arteriosclerosis, also known as medial arterial calcinosis, is a condition where the
tunica media The tunica media (Neo-Latin "middle coat"), or media for short, is the middle tunica (layer) of an artery or vein. It lies between the internal elastic lamina of the tunica intima on the inside and the tunica externa on the outside. Artery The ...
layer of blood vessels calcifies, visible on plain radiography or sectional tomography, and can sometimes be detected in dental panoramic radiographs. Unlike atherosclerosis, which affects the tunica intima and alters the vessel lumen, this condition is associated with
diabetes mellitus Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained hyperglycemia, high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or th ...
or
chronic kidney disease Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...
, and dental treatment is safe when the patient's diabetes is well-managed.


Epidemiology

The prevalence of Mönckeberg's arteriosclerosis increases with age and is more frequent in
diabetes mellitus Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained hyperglycemia, high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or th ...
, chronic kidney disease,
systemic lupus erythematosus Lupus, formally called systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common ...
, chronic inflammatory conditions, hypervitaminosis D (high vitamin D) and rare genetic disorders, such as Keutel syndrome. The prevalence of Mönckeberg's arteriosclerosis in the general population has been estimated as <1% on the basis of an ankle brachial pressure index >1.5; however the validity of this criterion is questionable. Increased use of long term corticosteroids have also been implicated in the development of Mönckeberg's arteriosclerosis. Animal studies have also suggested genetics may have a role in the development of Mönckeberg arteriosclerosis. Specific genetic mutations in the cardiovascular related genes VKORC1, NT5E, and ABCC6 have a potential role in the development of the disease.


References


External links

{{Vascular diseases Vascular diseases