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 Reason for visit: Patient is a 55 year old male who presented with persistent pains and

numbness in different body parts 1 week prior to consultation.


 History of Present Illness:
o Patient presented to the OPD with chief complaint of persisting pains and
numbness in different body parts 1 week before consultation.
o 1 month before hospital visit, he developed generalized headache and nape pains,
which were also associated with low back pains, and burning sensation on both
legs.
o Hospital laboratories show borderline high cholesterol: 230mg/dl and LDL:
140mg/dl; with Chest X-ray, PA view: Impression: Cardiac Enlargement.
 PMH/PSH:
o Family had a history of Heart disease.
 Patient’s father died of the disease at age 50.
 Patient’s brother has heart disease.
o 15 pack years smoking history
 Meds and Allergies
o Patient took Paracetamol 500mg, but medicine only brought temporary and
partial relief.
 Social/Habits/Other
o Patient lives with his wife; they have 3 young children
o Works as a manager in a big company
o Smoking as above
o Occasional drinker consuming 10 bottles
o No drug use
o Mostly eats instant noodles, fried porkchop with unlimited rice
 Family history
o With family history of cardiovascular disease, father and brother
 Physical Exam
o High BP: 160/90, Pulse 88 regular, weight 90kgs, Height: 168 cm, RR:20
o Chest findings: symmetrical chest expansion; clear and equal breath sounds
o CV: positive dynamic precordium; regular rate and rhythm; negative
tachycardia, murmurs
o Abdomen: globular, regular bowel sounds
o Skin and Extremities: warm, with good turgor; pink nailbeds; full pulses
o HEENT: Pink conjunctiva, dry cornea; pupils reactive to light; moist lips and
mucosa
 Labs and Imaging of note:
o Laboratories show borderline high cholesterol: 230mg/dl and LDL: 140mg/dl;
with Chest X-ray, PA view: Impression: Cardiac Enlargement.
 Assessment and Suggested treatment plan for the patient
1. Hypertension stage 2: also known as late high blood pressure or severe high
blood pressure, is generally characterized by a systolic blood pressure value
greater than 159 mm Hg, or a diastolic blood pressure value of 99 mmHg.
 Plan: Lifestyle changes including quitting smoking; maintaining a healthy
weight; dietary changes such as consuming a diet rich in fruits,
vegetables, and low-fat dairy products; and limiting salt. Limit alcohol
intake. Exercise at least 30 minutes per day. Smoking cessation.
2. Obese Class 1: low-risk obesity, if BMI is 30.0 to 34.9. with patient BMI: 31.9
 Plan: Reducing the intake of calories, reducing fat, carbohydrate
(especially those with a high glycemic index), protein or alcohol intake.
Gradually build up exercise as personal fitness allows.

 Other treatment plans


o Avoid stress and frustration as these can be triggers to unhealthy eating
behaviors. Keeping self occupied with enjoyable activities such as sports or
socializing with friends and family can help achieve a healthier lifestyle. If eating
excessively is unavoidable due to stress could consider enrolling in relaxation
programs or find other means as outlet of stress.

 Disposition: Return to clinic for follow-up check-up

Discussion:
Biochemistry of Hypertension

Cholesterol is an amphipathic (both hydrophobic and hydrophilic parts) lipid and as such is an
essential structural component of membranes, where it is important for the maintenance of
the correct permeability and fluidity, and of the outer layer of plasma lipoproteins. It is
synthesized in many tissues from acetyl-CoA and is the precursor of all other steroids in the
body, including corticosteroids, sex hormones, bile acids, and vitamin D.

A little more than half the cholesterol of the body arises by synthesis (about 700 mg/d), and the
remainder is provided by the average diet.

Typical product of animal metabolism, cholesterol occurs in foods of animal origin such as egg
yolk, meat, liver, and brain.

Synthesis of Cholesterol

27-carbon compound consisting of 4 rings and a side chain.

It is synthesized from acetyl- CoA by a pathway that may be divided into five steps:
(1) synthesis of mevalonate from acetyl-CoA: HMG-CoA (3-hydroxy- 3-
methylglutaryl-CoA) is formed by the reactions used in mitochondria to synthesize
ketone bodies. However, since cholesterol synthesis is extramitochondrial, the two
pathways are distinct. Initially, two molecules of acetyl-CoA condense to form
acetoacetyl-CoA catalyzed by cytosolic thiolase. Acetoacetyl-CoA condenses with a
further molecule of acetyl-CoA catalyzed by HMG-CoA synthase to form HMG-CoA,
which is reduced to mevalonate by NADPH in a reaction catalyzed by HMG-CoA
reductase. Next step is the principal regulatory step in the pathway of cholesterol
synthesis and is the site of action of the most effective class of cholesterol-lowering
drugs, the statins, which are HMG-CoA reductase inhibitors

(2) formation of isoprenoid units from mevalonate by loss of CO2: Mevalonate is


phosphorylated sequentially using ATP by three kinases, and after decarboxylation the active
isoprenoid unit, isopentenyl diphosphate, is formed.

(3) condensation of six isoprenoid units form squalene: Isopentenyl diphosphate is isomerized
by a shift of the double bond to form dimethylallyl diphosphate, and then condensed with
another molecule of isopentenyl diphosphate to form the 10-carbon intermediate geranyl
diphosphate (Figure 26–2). A further condensation with isopentenyl diphosphate forms farnesyl
diphosphate. Two molecules of farnesyl diphosphate condense at the diphosphate end to form
squalene. Initially, inorganic pyrophosphate is eliminated, forming presqualene diphosphate,
which is then reduced by NADPH with elimina- tion of a further inorganic pyrophosphate
molecule.

(4) cyclization of squalene give rise to the parent steroid, lanosterol: Squalene can fold into a
structure that closely resembles the steroid nucleus (Figure 26–3). Before ring closure occurs,
squalene is converted to squalene 2,3-epoxide by a mixed-function oxidase in the endoplasmic
reticulum, squalene epoxidase. The methyl group on C14 is transferred to C13 and that on C8 to
C14 as cyclization occurs, catalyzed by oxidosqualene-lanosterol cyclase.

(5) formation of cholesterol from lanosterol: The formation of cholesterol from lanosterol takes
place in the membranes of the endoplasmic reticulum and involves changes in the steroid nucleus
and the side chain (Figure 26–3). The methyl groups on C14 and C4 are removed to form 14-
desmethyl lanosterol and then zymosterol. The double bond at C8 ́C9 is subse- quently moved to
C5 ́C6 in two steps, forming desmosterol. Finally, the double bond of the side chain is reduced,
produc- ing cholesterol.

Plasma low-density lipoprotein (LDL) is the vehicle that supplies cholesterol and cholesteryl
ester to many tissues. Free cholesterol is removed from tissues by plasma high-density
lipoprotein (HDL) and transported to the liver, where it is eliminated from the body either
unchanged or after conversion to bile acids in the process known as reverse cholesterol
transport. Cholesterol is a major constituent of gallstones. However, its chief role in pathologic
processes is as a factor in the genesis of atherosclerosis of vital arteries, causing
cerebrovascular, coronary, and peripheral vascular disease.

Apolipoprotein B is the main structural surface protein found on all beta-lipoproteins


(Chylomicrons, VLDLs, IDLs and LDLs). Beta-lipoproteins are the lipoproteins capable of
trafficking cholesterol into the artery wall and hence if present in increased numbers, they
are the cause of atherosclerosis.
However there are two types of apolipoprotein B. One is produced in the liver and is called
apolipoprotein B 100 and the other is produced in the small intestine, which is termed
apolipoprotein B 48, because it is a shortened version of apoB which has 48% of the molecular
weight of apoB 100.

Since the lipoprotein produced in the intestine is the chylomicron, the apoB 48 particles are
chylomicrons of intestinal origin. VLDLs containing apoB100 are produced in the liver. After
VLDLs are excreted and undergo lipolysis (hydrolysis or removal of TG and phospholipids) they
become IDLs and LDLs. Thus there is a single molecule of apoB 100 on each VLDL, IDL and LDL
and a single molecule of apoB48 on each chylomicron.

This has consequences because LDL receptors remove beta-lipoproteins from plasma by
recognizing and attaching to the surface charges on certain segments of the apoB 100
molecule. ApoB48 is a shortened apoB100 and hence has a different conformation (lacks the
segment recognized by LDL receptors) present on apoB100 and is therefore apoB48 is not
recognized by LDL receptors. However, chylomicrons have a high content of apolipoprotein E
and LDL receptors also recognize and internalize apoE-containing lipoproteins. Thus the liver
LDL- receptors internalize chylomicrons by attaching to apoE and they internalize VLDLs by
attaching to apoB100 or apoE and they internalize LDLs by attaching to apoB100.

In FH, a condition characterized by very high levels of cholesterol in the blood due to mutations
in the LDL Receptor gene. The hereditary forms of hypercholesterolemia is caused by mutations
in the:

 APOB gene: provides instructions for making two versions of the apolipoprotein B protein, a
short version called apolipoprotein B-48 and a longer version known as apolipoprotein B-
100.
 LDLRAP1 gene: provides instructions for making a protein that helps remove cholesterol
from the bloodstream. The function of the LDLRAP1 protein is particularly important in the
liver, which is the organ responsible for clearing most excess cholesterol from the body.
 PCSK9 gene: provides instructions for making a protein that helps regulate the amount of
cholesterol in the bloodstream by controling the number of low-density lipoprotein
receptors. Studies suggest that the PCSK9 protein helps control blood cholesterol levels by
breaking down low-density lipoprotein receptors before they reach the cell surface.
However, most cases of high cholesterol are not caused by a single inherited condition, but
result from a combination of lifestyle choices and the effects of variations in many genes.

Role of Lipoprotein in Atherosclerosis


LDL cholesterol normally circulates in the body for 2.5 days, and subsequently the
apolipoprotein B portion of LDL cholesterol binds to the LDL receptor on the liver cells,
triggering its uptake and digestion.[7] This process results in the removal of LDL from the
circulatory system. Synthesis of cholesterol by the liver is suppressed in the HMG-CoA
reductase pathway.[15] In FH, LDL receptor function is reduced or absent,[7] and LDL circulates
for an average duration of 4.5 days, resulting in significantly increased level of LDL cholesterol
in the blood with normal levels of other lipoproteins.[4] In mutations of ApoB, reduced binding
of LDL particles to the receptor causes the increased level of LDL cholesterol. It is not known
how the mutation causes LDL receptor dysfunction in mutations of PCSK9 and ARH.

ApoB100 is found in lipoproteins originating from the liver (VLDL, IDL, LDL[13]). Importantly,
there is one ApoB100 molecule per hepatic-derived lipoprotein. Hence, using that fact, one can
quantify the number of lipoprotein particles by noting the total ApoB100 concentration in the
circulation. Since there is one and only one ApoB100 per particle, the number of particles is
reflected by the ApoB100 concentration. The same technique can be applied to individual
lipoprotein classes (e.g. LDL) and thereby enable one to count them as well.

It is well established that ApoB100 levels are associated with coronary heart disease, and are
even a better predictor of it than is LDL level.[citation needed] A naive way of explaining this
observation is to use the idea that ApoB100 reflects lipoprotein particle number (independent
of their cholesterol content). In this way, one can infer that the number of ApoB100-containing
lipoprotein particles is a determinant of atherosclerosis and heart disease.

One way to explain the above is to consider that large numbers of lipoprotein particles, and, in
particular large numbers of LDL particles, lead to competition at the LDL receptor of peripheral
cells. Since such a competition will prolong the residence time of LDL particles in the circulation,
it may lead to greater opportunity for them to undergo oxidation and/or other chemical
modifications. Such modifications may lessen the particles' ability to be cleared by the classic
LDL receptor and/or increase their ability to interact with so-called "scavenger" receptors. The
net result is shunting of LDL particles to these scavenger receptors. Scavenger receptors
typically are found on macrophages, with cholesterol laden macrophages being better known
as "foam cells". Foam cells characterize atherosclerotic lesions. In addition to this possible
mechanism of foam cell generation, an increase in the levels of chemically modified LDL
particles may also lead to an increase in endothelial damage. This occurs as a result of
modified-LDL's toxic effect on vascular endothelium as well its ability both to recruit immune
effector cells and to promote platelet activation.

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