Gastrointestinal Hormones.

A mixture of several important gastrointestinal

hormones—gastrin, secretin, cholecystokinin, and gastric inhibitory peptide (which
seems to be the most potent)—causes a moderate increase in insulin secretion. These
hormones are released in the gastrointestinal tract after a person eats a meal. They
then cause an “anticipatory” increase in blood insulin in preparation for the glucose and
amino acids to be absorbed from the meal. These gastrointestinal hormones generally
act the same way as amino acids to increase the sensitivity of insulin response to
increased blood glucose, almost doubling the rate of insulin secretion as the blood
glucose level rises.

Gastrin, Secretin and Pancreozymin: Are gastrointestinal peptides which act

as hormones which stimulate secretion of bile and other enzymes of digestive juices.

Calcium stimulates gastrin (and therefore gastric acid) secretion. There is an

association between chronic hypercalcaemia and peptic ulceration. The patient may
complain of constipation and abdominal pain. Hypercalcaemia may also present as an
acute abdomen.

● Gastrin, which is carried by the bloodstream to the parietal cells of the stomach; its
action is mediated by histamine.

Gastrin secretion is inhibited (by negative feedback) by acid in the pylorus.

Calcium also stimulates gastrin secretion and this may explain the relatively high
incidence of peptic ulceration in patients with chronic hypercalcaemia.

Hypersecretion of gastric juice may cause duodenal ulceration.

However, there is overlap between the amount of acid secreted in normal subjects and
in those with duodenal ulceration.

The estimation of gastric acidity is of very limited diagnostic value.

In the very rare Zollinger–Ellison syndrome, acid secretion is very high due to excessive
gastrin produced by a gastrinoma – a tumour more usually involving the pancreas or
duodenum.

Hyposecretion of gastric juice occurs most commonly in association with pernicious

anaemia, due to the formation of antibodies to the parietal cells of the gastric mucosa.

Extensive carcinoma of the stomach and chronic gastritis may also cause gastric
hyposecretion.
Plasma gastrin concentrations are raised, because reduced acid secretion causes the
loss of negative feedback inhibition.

● Gastrin is released from the gastrin-secreting G cells in the gastric antrum in response
to distension and to protein.

It stimulates the contraction of the stomach muscles and the secretion of gastric acid.
Acid inhibits gastrin release by negative feedback.

Fasting plasma gastrin concentrations are up to 30 times the upper reference limit in
Zollinger– Ellison syndrome.

Plasma concentrations more than 1000 µg/L with acid hypersecretion strongly support
this diagnosis.

However, high plasma gastrin concentrations may also be caused by hypochlorhydria,

for example atrophic gastritis, pernicious anaemia or post vagotomy.

H2 blockers and proton pump inhibitors are usually stopped prior to sampling.

Gastrin is secreted by the “G” cells of the antrum of the stomach in response to stimuli
associated with ingestion of a meal, such as distention of the stomach, the products of
proteins, and gastrin releasing peptide, which is released by the nerves of the gastric
mucosa during vagal stimulation.

The primary actions of gastrin are:

(1) stimulation of gastric acid secretion and

(2) stimulation of growth of the gastric mucosa.

Stomach wall stretch and the presence of certain types of foods in the stomach—
particularly digestive products of meat—elicit release of a hormone called gastrin from
the antral mucosa. This has potent effects to cause secretion of highly acidic gastric
juice by the stomach glands.

Gastrin also has mild to moderate stimulatory effects on motor functions in the body of
the stomach. Most important, it seems to enhance the activity of the pyloric pump. Thus,
it, too, probably promotes stomach emptying.
Emptying of the stomach is controlled only to a moderate degree by stomach factors
such as the degree of filling in the stomach and the excitatory effect of gastrin on
stomach peristalsis.

The pyloric glands secrete mainly mucus for protection of the pyloric mucosa from the
stomach acid.

Pyloric glands also secrete the hormone gastrin.

Probably the most potent mechanism for stimulating histamine secretion is by the
hormonal substance gastrin, which is formed almost entirely in the antral portion of the
stomach mucosa in response to proteins in the foods being digested.

Stimulation of Acid Secretion by Gastrin.

Gastrin is itself a hormone secreted by gastrin cells, also called G cells.

These cells are located in the pyloric glands in the distal end of the stomach.

Gastrin is a large polypeptide secreted in two forms: a large form called G-34, which
contains 34 amino acids, and a smaller form, G-17, which contains 17 amino acids.

Although both of these are important, the smaller is more abundant.

When meats or other protein-containing foods reach the antral end of the stomach,
some of the proteins from these foods have a special stimulatory effect on the gastrin
cells in the pyloric glands to cause release of gastrin into the digestive juices of the
stomach.

The vigorous mixing of the gastric juices transports the gastrin rapidly to the ECL cells
in the body of the stomach, causing release of histamine directly into the deep oxyntic
glands.

The histamine then acts quickly to stimulate gastric hydrochloric acid secretion.

The gastrin mechanism, all of which in turn cause secretion of gastric juice during
several hours while food remains in the stomach.

The gastric phase of secretion accounts for about 70 per cent of the total gastric
secretion associated with eating a meal and therefore accounts for most of the total
daily gastric secretion of about 1500 milliliters.

Gastrin, cholecystokinin, and secretin are all large polypeptides with approximate
molecular weights, respectively, of 2000, 4200, and 3400.
The terminal five amino acids in the gastrin and cholecystokinin molecular chains are
the same.

The functional activity of gastrin resides in the terminal four amino acids, and the activity
for cholecystokinin resides in the terminal eight amino acids.

All the amino acids in the secretin molecule are essential.

A synthetic gastrin, composed of the terminal four amino acids of natural gastrin plus
the amino acid alanine, has all the same physiologic properties as the natural gastrin.
This synthetic product is called Pentagastrin.

Secretin was the first gastrointestinal hormone discovered and is secreted by the “S”
cells in the mucosa of the duodenum in response to acidic gastric juice emptying into
the duodenum from the pylorus of the stomach.

Secretin has a mild effect on motility of the gastrointestinal tract and acts to promote
pancreatic secretion of bicarbonate which in turn helps to neutralize the acid in the small
intestine.

Other possible inhibitors of stomach emptying are the hormones secretin and gastric
inhibitory peptide (GIP).

Secretin is released mainly from the duodenal mucosa in response to gastric acid
passed from the stomach through the pylorus.

GIP has a general but weak effect of decreasing gastrointestinal motility.

Secretin and glucagon inhibit small intestinal motility.

The physiologic importance of each of these hormonal factors for controlling motility is
still questionable.

The presence of acid, fat, protein breakdown products, hyperosmotic or hypo-osmotic

fluids, or any irritating factor in the upper small intestine causes release of several
intestinal hormones.

One of these is secretin, which is especially important for control of pancreatic

secretion. However, secretin opposes stomach secretion.

All the amino acids in the secretin molecule are essential.

Secretin is a polypeptide, containing 27 amino acids (molecular weight about 3400),
present in an inactive form, prosecretin, in so-called S cells in the mucosa of the
duodenum and jejunum.

When acid chyme with pH less than 4.5 to 5.0 enters the duodenum from the stomach,
it causes duodenal mucosal release and activation of secretin, which is then absorbed
into the blood.

The one truly potent constituent of chyme that causes this secretin release is the
hydrochloric acid from the stomach.

Secretin in turn causes the pancreas to secrete large quantities of fluid containing a
high concentration of bicarbonate ion (up to 145 mEq/L) but a low concentration of
chloride ion.

The secretin mechanism is especially important for two reasons: First, secretin begins
to be released from the mucosa of the small intestine when the pH of the duodenal
contents falls below 4.5 to 5.0, and its release increases greatly as the pH falls to 3.0.

This immediately causes copious secretion of pancreatic juice containing abundant

amounts of sodium bicarbonate.

The net result is then the following reaction in the duodenum: Then the carbonic acid
immediately dissociates into carbon dioxide and water.

The carbon dioxide is absorbed into the blood and expired through the lungs, thus
leaving a neutral solution of sodium chloride in the duodenum. In this way, the acid
contents emptied into the duodenum from the stomach become neutralized, so that
further peptic digestive activity by the gastric juices in the duodenum is immediately
blocked. Because the mucosa of the small intestine cannot withstand the digestive
action of acid gastric juice, this is an essential protective mechanism to prevent
development of duodenal ulcers.

Bicarbonate ion secretion by the pancreas provides an appropriate pH for action of the
pancreatic digestive enzymes, which function optimally in a slightly alkaline or neutral
medium, at a pH of 7.0 to 8.0. Fortunately, the pH of the sodium bicarbonate secretion
averages 8.0.

The hormone secretin that also stimulates pancreatic secretion increases bile secretion,
sometimes more than doubling its secretion for several hours after a meal.
This increase in secretion is almost entirely secretion of a sodium bicarbonate-rich
watery solution by the epithelial cells of the bile ductules and ducts, and not increased
secretion by the liver parenchymal cells themselves.

The bicarbonate in turn passes into the small intestine and joins the bicarbonate from
the pancreas in neutralizing the hydrochloric acid from the stomach.

Thus, the secretin feedback mechanism for neutralizing duodenal acid operates not only
through its effects on pancreatic secretion but also to a lesser extent through its effect
on secretion by the liver ductules and ducts.

The presence of acid in the small intestine liberates secretin from the intestinal mucosa,
which then passes by way of the blood to the pancreas to promote rapid secretion of
pancreatic juice.

This juice also contains a high concentration of sodium bicarbonate, thus making still
more sodium bicarbonate available for neutralization of the acid.

Cholecystokinin is secreted by “I” cells in the mucosa of the duodenum and jejunum
mainly in response to digestive products of fat, fatty acids, and monoglycerides in the
intestinal contents.

This hormone strongly contracts the gallbladder, expelling bile into the small intestine
where the bile in turn plays important roles in emulsifying fatty substances, allowing
them to be digested and absorbed.

Cholecystokinin also inhibits stomach contraction moderately. Therefore, at the same

time that this hormone causes emptying of the gallbladder, it also slows the emptying of
food from the stomach to give adequate time for digestion of the fats in the upper
intestinal tract.

Most of these are peptide hormones, including cholecystokinin, vasoactive intestinal

peptide, gastrin, and secretin. These same hormones control specific motor and
secretory activities of the gut.

Precisely which hormones cause the hormonal feedback inhibition of the stomach is not
fully clear. The most potent appears to be cholecystokinin (CCK), which is released from
the mucosa of the jejunum in response to fatty substances in the chyme.

The terminal five amino acids in the gastrin and cholecystokinin molecular chains are
the same.
The functional activity of gastrin resides in the terminal four amino acids, and the activity
for cholecystokinin resides in the terminal eight amino acids.

The presence of food in the upper small intestine also causes a second hormone,
cholecystokinin, a polypeptide containing 33 amino acids, to be released from yet
another group of cells, the I cells, in the mucosa of the duodenum and upper jejunum.
This release of cholecystokinin results especially from the presence of proteoses and
peptones (products of partial protein digestion) and long-chain fatty acids in the chyme
coming from the stomach.

Cholecystokinin, like secretin, passes by way of the blood to the pancreas but instead of
causing sodium bicarbonate secretion causes mainly secretion of still much more
pancreatic digestive enzymes by the acinar cells.

This effect is similar to that caused by vagal stimulation but even more pronounced,
accounting for 70 to 80 per cent of the total secretion of the pancreatic digestive
enzymes after a meal.

The most potent stimulus for causing the gallbladder contractions is the hormone
cholecystokinin.

The stimulus for cholecystokinin entry into the blood from the duodenal mucosa is mainly the
presence of fatty foods in the duodenum.

In addition to cholecystokinin, the gallbladder is stimulated less strongly by

acetylcholine-secreting nerve fibers from both the vagi and the intestinal enteric nervous
system.

They are the same nerves that promote motility and secretion in other parts of the upper
gastrointestinal tract.

Cholecystokinin is released mainly in response to fat entering the duodenum and has a direct
effect on the feeding centers to reduce subsequent eating.

Studies in experimental animals suggest that CCK may decrease feeding mainly by activation of
the melanocortin pathway in the hypothalamus.
 Disorders of Swallowing and of the Esophagus

Paralysis of the Swallowing Mechanism:

1. Damage to the 5th, 9th, or 10th cerebral nerve can cause paralysis of significant portions
of the swallowing mechanism.
2. Also, a few diseases, such as poliomyelitis or encephalitis, can prevent normal
swallowing by damaging the swallowing center in the brain stem.
3. Finally, paralysis of the swallowing muscles, as occurs in muscle dystrophy or in failure
of neuromuscular transmission in myasthenia gravis or botulism, can also prevent
normal swallowing.
4. When the swallowing mechanism is partially or totally paralyzed, the abnormalities that
can occur include;
(1) complete abrogation of the swallowing act so that swallowing cannot occur,
(2) failure of the glottis to close so that food passes into the lungs instead of the
esophagus, and
(3) failure of the soft palate and uvula to close the posterior nares so that food refluxes
into the nose during swallowing.
5. One of the most serious instances of paralysis of the swallowing mechanism occurs
when patients are under deep anesthesia.
6. Often, while on the operating table, they vomit large quantities of materials from the
stomach into the pharynx; then, instead of swallowing the materials again, they simply
suck them into the trachea because the anesthetic has blocked the reflex mechanism of
swallowing.
7. As a result, such patients occasionally choke to death on their own vomitus.

Achalasia and Megaesophagus:

1. Achalasia is a condition in which the lower esophageal sphincter fails to relax

during swallowing.
2. As a result, food swallowed into the esophagus then fails to pass from the
esophagus into the stomach.
3. Pathological studies have shown damage in the neural network of the myenteric
plexus in the lower two thirds of the esophagus.
4. As a result, the musculature of the lower esophagus remains spastically
contracted, and the myenteric plexus has lost its ability to transmit a signal to
cause “receptive relaxation” of the gastroesophageal sphincter as food
approaches this sphincter during swallowing.
5. When achalasia becomes severe, the esophagus often cannot empty the
swallowed food into the stomach for many hours, instead of the few seconds that
is the normal time.
 6. Over months and years, the esophagus becomes tremendously enlarged until it
often can hold as much as 1 liter of food, which often becomes putridly infected
during the long periods of esophageal stasis.
7. The infection may also cause ulceration of the esophageal mucosa, sometimes
leading to severe substernal pain or even rupture and death.
8. Considerable benefit can be achieved by stretching the lower end of the
esophagus by means of a balloon inflated on the end of a swallowed esophageal
tube. Antispasmotic drugs (drugs that relax smooth muscle) can also be helpful.

Gastric Atrophy:

1. In many people who have chronic gastritis, the mucosa gradually becomes more and
more atrophic until little or no gastric gland digestive secretion remains.
2. It is also believed that some people develop autoimmunity against the gastric mucosa,
this also leading eventually to gastric atrophy.
3. Loss of the stomach secretions in gastric atrophy leads to achlorhydria and,
occasionally, to pernicious anemia.

Achlorhydria (and Hypochlorhydria).

1. Achlorhydria means simply that the stomach fails to secrete hydrochloric acid; it is
diagnosed when the pH of the gastric secretions fails to decrease below 6.5 after
maximal stimulation.
2. Hypochlorhydria means diminished acid secretion. When acid is not secreted, pepsin
also usually is not secreted; even when it is, the lack of acid prevents it from functioning
because pepsin requires an acid medium for activity.

Pernicious Anemia in Gastric Atrophy:

1. Pernicious anemia is a common accompaniment of gastric atrophy and achlorhydria.

2. Normal gastric secretions contain a glycoprotein called intrinsic factor, secreted by the
same parietal cells that secrete hydrochloric acid.
3. Intrinsic factor must be present for adequate absorption of vitamin B12 from the ileum.
4. That is, intrinsic factor combines with vitamin B12 in the stomach and protects it from
being digested and destroyed as it passes into the small intestine.
5. Then, when the intrinsic factor–vitamin B12 complex reaches the terminal ileum, the
intrinsic factor binds with receptors on the ileal epithelial surface.
6. This in turn makes it possible for the vitamin B12 to be absorbed.
7. In the absence of intrinsic factor, only about 1/50 of the vitamin B12 is absorbed. And,
without intrinsic factor, an adequate amount of vitamin B12 is not made available from
the foods to cause young, newly forming red blood cells to mature in the bone marrow.
8. The result is pernicious anemia.
Peptic Ulcer:
1. A peptic ulcer is an excoriated area of stomach or intestinal mucosa caused principally
by the digestive action of gastric juice or upper small intestinal secretions.
2. In addition, peptic ulcers frequently occur along the lesser curvature of the antral end of
the stomach or, more rarely, in the lower end of the esophagus where stomach juices
frequently reflux.
3. A type of peptic ulcer called a marginal ulcer also often occurs wherever a surgical
opening such as a gastrojejunostomy has been made between the stomach and the
jejunum of the small intestine.

Pancreatitis:
1. Pancreatitis means inflammation of the pancreas, and this can occur in the form of either
acute pancreatitis or chronic pancreatitis.
2. The most common cause of pancreatitis is drinking excess alcohol, and the second
most common cause is blockage of the papilla of Vater by a gallstone; the two together
account for more than 90 per cent of all cases.
3. When a gallstone blocks the papilla of Vater, this blocks the main secretory duct from the
pancreas as well as the common bile duct.
4. The pancreatic enzymes are then dammed up in the ducts and acini of the pancreas.
5. Eventually, so much trypsinogen accumulates that it overcomes the trypsin inhibitor in
the secretions, and a small quantity of trypsinogen becomes activated to form trypsin.
6. Once this happens, the trypsin activates still more trypsinogen as well as
chymotrypsinogen and carboxypolypeptidase, resulting in a vicious circle until most of
the proteolytic enzymes in the pancreatic ducts and acini become activated.
7. These enzymes rapidly digest large portions of the pancreas itself, sometimes
completely and permanently destroying the ability of the pancreas to secrete digestive
enzymes.

Vomiting
1. Vomiting is the means by which the upper gastrointestinal tract rids itself of its contents
when almost any part of the upper tract becomes excessively irritated, overdistended, or
even overexcitable.
2. Excessive distention or irritation of the duodenum provides an especially strong stimulus
for vomiting.
3. The sensory signals that initiate vomiting originate mainly from the pharynx, esophagus,
stomach, and upper portions of the small intestines.
4. The nerve impulses are transmitted,by both vagal and sympathetic afferent nerve fibers
to multiple distributed nuclei in the brain stem that all together are called the “vomiting
center.”
 5. From here, motor impulses that cause the actual vomiting are transmitted from the
vomiting center by way of the 5th, 7th, 9th, 10th, and 12th cranial nerves to the upper
gastrointestinal tract, through vagal and sympathetic nerves to the lower tract, and
through spinal nerves to the diaphragm and abdominal muscles.

Exocrine Pancreas
The exocrine pancreas is a gland that produces digestive enzymes
and bicarbonate. It is an essential organ for the survival, adaptation,
and restoration of the organism. The exocrine pancreas’ function must
be evaluated in relationship to the endocrine pancreas, stomach,
intestines, liver, gallbladder, lungs, skin, joints, immunity, central
nervous system, autonomic nervous system, and endocrine system. It
affects or is solicited by each of these areas of the organism. From
this arises the role of the exocrine pancreas in the precritical and
critical terrain of numerous disorders from immunity to athropathies,
from digestive to mental. There are numerous signs and symptoms
according to the theory of endobiogeny that indicate the level of
insufficiency of oversolicitation of the exocrine pancreas. This, along
with clinical history and other signs and symptoms guide the
endobiogenist in a targeted and personalized selection of therapeutic
interventions that are efficient and polyvalent. A key index indirectly
related to the exocrine pancreas is the somatostatin index. The
formula and a discussion of high and low results is presented.

1. Proteases

Digestion of proteins is initiated by pepsin in the stomach, but the bulk

of protein digestion is due to the pancreatic proteases. Several
proteases are synthesized in the pancreas and secreted into the
lumen of the small intestine. The two major pancreatic proteases are
trypsin and chymotrypsin, which are synthesized and packaged into
secretory vesicles as the inactive proenzymes trypsinogen and
chymotrypsinogen.
As you might anticipate, proteases are rather dangerous enzymes to
have in cells, and packaging of an inactive precursor is a way for the
cells to safely handle these enzymes. The secretory vesicles also
contain a trypsin inhibitor which serves as an additional safeguard
should some of the trypsinogen be activated to trypsin; following
exocytosis this inhibitor is diluted out and becomes ineffective - the pin
is out of the grenade.

Once trypsinogen and chymotrypsinogen are released into the lumen

of the small intestine, they must be converted into their active forms in
order to digest proteins. Trypsinogen is activated by the enzyme
enterokinase, which is embedded in the intestinal mucosa.

Once trypsin is formed it activates chymotrypsinogen, as well as

additional molecules of trypsinogen. The net result is a rather
explosive appearance of active protease once the pancreatic
secretions reach the small intestine.

Trypsin and chymotrypsin digest proteins into peptides and peptides

into smaller peptides, but they cannot digest proteins and peptides to
single amino acids. Some of the other proteases from the pancreas,
for instance carboxypeptidase, have that ability, but the final digestion
of peptides into amino acids is largely the effect of peptidases on the
surface of small intestinal epithelial cells. More on this later.

2. Pancreatic Lipase

A major component of dietary fat is triglyceride, or neutral lipid. A

triglyceride molecule cannot be directly absorbed across the intestinal
mucosa. Rather, it must first be digested into a 2-monoglyceride and
two free fatty acids. The enzyme that performs this hydrolysis is
pancreatic lipase, which is delivered into the lumen of the gut as a
constituent of pancreatic juice.

Sufficient quantities of bile salts must also be present in the lumen of

the intestine in order for lipase to efficiently digest dietary triglyceride
and for the resulting fatty acids and monoglyceride to be absorbed.
This means that normal digestion and absorption of dietary fat is
critically dependent on secretions from both the pancreas and liver.

Pancreatic lipase has recently been in the limelight as a target for

management of obesity. The drug orlistat (Xenical) is a pancreatic
lipase inhibitor that interferes with digestion of triglyceride and thereby
reduces absorption of dietary fat. Clinical trials support the contention
that inhibiting lipase can lead to significant reductions in body weight
in some patients.

3. Amylase

The major dietary carbohydrate for many species is starch, a storage

form of glucose in plants. Amylase (technically alpha-amylase) is the
enzyme that hydrolyses starch to maltose (a glucose-glucose
disaccharide), as well as the trisaccharide maltotriose and small
branchpoints fragments called limit dextrins. The major source of
amylase in all species is pancreatic secretions, although amylase is
also present in saliva of some animals, including humans.

Other Pancreatic Enzymes

In addition to the proteases, lipase and amylase, the pancreas

produces a host of other digestive enzymes, including ribonuclease,
deoxyribonuclease, gelatinase and elastase.
Bicarbonate and Water

Epithelial cells in pancreatic ducts are the source of the bicarbonate

and water secreted by the pancreas. Bicarbonate is a base and critical
to neutralizing the acid coming into the small intestine from the
stomach. The mechanism underlying bicarbonate secretion is
essentially the same as for acid secretion by parietal cells in the
stomach and is dependent on the enzyme carbonic anhydrase. In
pancreatic duct cells, the bicarbonate is secreted into the lumen of the
duct and hence into pancreatic juice.

Pancreatic diseases
Pancreatic diseases are diseases that affect the pancreas, an organ in most vertebrates and in
humans and other mammals located in the abdomen. The pancreas plays a role in the digestive and
endocrine system, producing enzymes which aid the digestion process and the hormone insulin,
which regulates blood sugar levels. The most common pancreatic disease is pancreatitis, an
inflammation of the pancreas which could come in acute or chronic form. Other pancreatic diseases
include diabetes mellitus, exocrine pancreatic insufficiency, cystic fibrosis, pseudocysts, cysts,
congenital malformations, tumors including pancreatic cancer, and hemosuccus pancreaticus.

Pancreatitis

Pancreatitis is inflammation of the pancreas. There are two forms of pancreatitis, which are different
in causes and symptoms, and require different treatment:
● Acute pancreatitis is a rapid-onset inflammation of the pancreas, most frequently caused
by alcoholism or gallstones. Less frequent but important causes are hypertriglyceridemia,
drugs, infections.
 ● Chronic pancreatitis is a long-standing inflammation of the pancreas.

Diabetes mellitus
The pancreas is central in the pathophysiology of both major types of diabetes mellitus. In type 1
diabetes mellitus, there is direct damage to the endocrine pancreas that results in insufficient insulin
synthesis and secretion. Type 2 diabetes mellitus, which begins with insulin resistance, is
characterized by the ultimate failure of pancreatic β cells to match insulin production with insulin
demand.

Exocrine pancreatic insufficiency

Exocrine pancreatic insufficiency (EPI) is the inability to properly digest food due to a lack of
digestive enzymes made by the pancreas. EPI is found in humans afflicted with cystic fibrosis and
Shwachman–Diamond syndrome. It is caused by a progressive loss of the pancreatic cells that
make digestive enzymes. Chronic pancreatitis is the most common cause of EPI in humans. Loss of
digestive enzymes leads to maldigestion and malabsorption of nutrients.

Cystic fibrosiS
Cystic fibrosis, is a hereditary disease that affects the entire body, causing progressive disability and
early death. It is caused by a mutation in the cystic fibrosis transmembrane conductance regulator
(CFTR) gene. The product of this gene helps create sweat, digestive juices, and mucus. The name
cystic fibrosis refers to the characteristic 'fibrosis' (tissue scarring) and cyst formation within the
pancreas, causing irreversible damage, and often resulting in painful inflammation (pancreatitis).

Pseudocysts
A pancreatic pseudocyst is a circumscribed collection of fluid rich in amylase and other pancreatic
enzymes, blood and necrotic tissue, typically located in the lesser sac.

Cysts
X-ray computed tomography (CT scan) findings of cysts in the pancreas are common, and often are
benign. In a study of 2,832 patients without pancreatic disease, 73 patients (2.6%) had cysts in the
[4]
pancreas. About 85% of these patients had a single cyst. Cysts ranged in size from 2 to 38 mm
(mean, 8.9 mm). There was a strong correlation between the presence of cysts and age. No cysts
were identified among patients less than 40 years of age, while 8.7 percent of the patients aged 80
to 89 years had a pancreatic cyst.
Cysts also may be present due to intraductal papillary mucinous neoplasm.

Congenital malformations
Pancreas divisum
Pancreas divisum is a malformation in which the pancreas fails to fuse. It is a rare condition that
affects only 6% of the world's population, and of these few, only 1% ever have symptoms that
require surgery.

Annular pancreas
Annular pancreas is characterized by a pancreas that encircles the duodenum. It results from an
embryological malformation in which the early pancreatic buds undergo inappropriate rotation and
fusion, which can lead to small bowel obstruction.

Tumors and cancer

● Pancreatic tumors (masses) including pancreatic cancer

Benign[edit]
● Serous cystadenoma of the pancreas
● Solid pseudopapillary neoplasm

Tumor predisposition

Zollinger-Ellison syndrome

Zollinger-Ellison syndrome is a collection of findings in individuals with gastrinoma, a tumor of the

gastrin-producing cells of the pancreas. Unbridled gastrin secretion results in elevated levels of the
hormone, and increased hydrochloric acid secretion from parietal cells of the stomach. It can lead to
ulceration and scarring of the stomach and intestinal mucosa.

Hemosuccus pancreaticus
Hemosuccus pancreaticus, also known as pseudohematobilia or Wirsungorrhage, is a rare cause of
hemorrhage in the gastrointestinal tract. It is caused by a bleeding source in the pancreas,
pancreatic duct, or structures adjacent to the pancreas, such as the splenic artery, that bleed into the
pancreatic duct. Patients with hemosuccus may develop symptoms of gastrointestinal hemorrhage,
such as blood in the stools, maroon stools, or melena. They may also develop abdominal pain.
Hemosuccus pancreaticus is associated with pancreatitis, pancreatic cancer and aneurysms of the
splenic artery. Angiography may be used to diagnose hemosuccus pancreaticus, where the celiac
axis is injected to determine the blood vessel that is bleeding. Concomitant embolization of the end
vessel may terminate the hemorrhage. Alternatively, a distal pancreatectomy may be required to
stop the hemorrhage.
What is steatorrhea?
You may not think much about the makeup of your stool. Most of it is water,
and the rest is a combination of:

● bacteria
● fats
● fiber
● mucus
● protein
● salts
● various cell linings

Too much fat in your feces is called steatorrhea.

It may be a result of overconsumption of fatty and greasy foods, or it can be a

sign of malabsorption. This means your body either isn’t absorbing nutrients
properly or isn’t making the enzymes or bile needed to digest food effectively.

If you’re experiencing steatorrhea, make an appointment to talk with your

doctor. They can help you figure out the underlying cause and recommend
treatment options.

What are the symptoms of

steatorrhea?
If you have steatorrhea, your stools may be:
 ● bulkier
● pale
● foul smelling
● floating

The stools also tend to be covered in a greasy film. You might even see drops
of oil in the water inside the toilet bowl.

Steatorrhea is only one of several common symptoms of malabsorption.

Others include:

● abdominal cramps
● diarrhea
● gas
● indigestion
● weight loss

What causes steatorrhea?

Too much fat in your stool suggests your digestive system isn’t breaking down
food adequately. Your body may not absorb the useful parts of the food you
eat, including dietary fat.

One of the most common causes of malabsorption is cystic fibrosis. This is an

inherited condition that affects your sweat and mucous glands, as well as
various organs in your body, including the pancreatic glands.
If steatorrhea is due to malabsorption, it can most often be related to problems
with pancreas function. The pancreatic juices are important in digesting fat
content.

Another cause of malabsorption that can lead to steatorrhea is chronic

pancreatitis. Pancreatitis is an inflammation of your pancreas, an organ near
your stomach. It releases enzymes to help you digest fat, protein, and
carbohydrates in your small intestine.

Chronic pancreatitis can have many different causes. Some examples include
alcohol use disorder, smoking, and family history.

Fatty stool is also a symptom of exocrine pancreatic insufficiency (EPI). EPI is

a condition where your pancreas doesn’t make or release enough of the
enzymes needed to help your digestive system break down food and absorb
nutrients.

With EPI, steatorrhea happens when your digestive system gets rid of too
many fats instead of absorbing them. This usually occurs when fat-digesting
enzymes in your pancreas drop to 5 to 10 percent of typical levels.

A few other causes of malabsorption include:

● Biliary atresia: a blockage in the ducts that carry bile (a fluid that helps
your body digest and get rid of certain waste products) from your liver to
your gallbladder
● Celiac disease: when you have a sensitivity to gluten, a protein in wheat
and certain other grains
● Crohn’s disease: one of several conditions under the label inflammatory
bowel disease, an inflammation of your gastrointestinal tract
 ● Lactose intolerance: the inability to digest a sugar in milk products
because you lack the enzyme lactase
● Whipple disease: a bacterial infection of your digestive system that
affects how your body breaks down fats and carbohydrates

How is steatorrhea diagnosed?

If you notice that your stool floats and appears greasy, pale, and abnormally
foul smelling, you should talk with your doctor.

This is especially true if you have other symptoms of malabsorption, such as

weight loss or cramps.

In addition to reviewing your medical history and symptoms, your doctor will
likely order two common tests for steatorrhea. One is a qualitative test of fecal
fat; the other is a quantitative test of fecal fat.

Qualitative test

The qualitative test measures the number of fat globules (drops) in one stool
sample.

Typical levels are fewer than 50 neutral fat globules and fewer than 100 fatty
acid fat globules, both as seen under a microscope.

Quantitative test
For a quantitative test, you must collect stool samples over a period of 2 to 4
days. All the samples are then studied to determine the total amount of fat in
each day’s stool.

Average test results would show 2 to 7 grams per 24 hours for adults, with fat
making up less than 20 percent of the solid stool sample.

For an infant, there should be less than 1 gram per 24 hours. For bottle-fed
babies, fat should make up 30 to 50 percent of the stool sample. For breastfed
babies, a normal result ranges from 10 to 40 percent.

D-xylose test

Your doctor might also recommend a D-xylose absorption test. This is another
test that’s done when malabsorption is suspected.

D-xylose is a kind of sugar. This test measures the levels of D-xylose in your
blood or urine.

Other tests

Your doctor may order other tests to make a diagnosis.

For example, if you have symptoms after eating wheat, your doctor can do
specific tests to check for celiac disease. The same is true for lactose
intolerance and other potential causes. Be sure to discuss these tests with
your doctor.
How is steatorrhea treated?
Treating steatorrhea is really about treating the underlying cause or causes of
this condition. And because malabsorption can have many causes, it will be
important to get a reliable diagnosis.

For diet-related causes, the treatment is usually a matter of avoiding the foods
that trigger your symptoms.

For example, if you’re lactose intolerant, you’ll need to avoid milk products or
perhaps consume them in very small doses. This will depend on the severity
of your lactose intolerance.

For celiac disease, avoiding wheat and other foods that contain gluten will be
your most effective treatment.

EPI is typically treated with medications, dietary changes, and nutrition

supplements. Often supplementary pancreatic enzymes may be prescribed.
Your treatment plan will depend on your symptoms and the cause behind your
EPI.

For causes such as cystic fibrosis or chronic pancreatitis, medications and

lifestyle changes will be necessary.

Malabsorption by the Small Intestinal Mucosa—Sprue

Occasionally, nutrients are not adequately absorbed from the small intestine even though the
food has become well digested.
Several diseases can cause decreased absorption by the mucosa; they are often classified
together under the general term “sprue.”
Malabsorption also can occur when large portions of the small intestine have been removed.

Nontropical Sprue.

❖ One type of sprue, called variously idiopathic sprue, celiac disease (in children), or
gluten enteropathy, results from the toxic effects of gluten present in certain types of
grains, especially wheat and rye.
❖ Only some people are susceptible to this effect, but in those who are susceptible, gluten
has a direct destructive effect on intestinal enterocytes.
❖ In milder forms of the disease, only the microvilli of the absorbing enterocytes on the villi
are destroyed, thus decreasing the absorptive surface area as much as twofold.
❖ In the more severe forms, the villi themselves become blunted or disappear altogether,
thus still further reducing the absorptive area of the gut.
❖ Removal of wheat and rye flour from the diet frequently results in cure within weeks,
especially in children with this disease.

Tropical Sprue.
❖ A different type of sprue called tropical sprue frequently occurs in the tropics and can
often be treated with antibacterial agents.
❖ Even though no specific bacterium has been implicated as the cause, it is believed that
this variety of sprue is usually caused by inflammation of the intestinal mucosa resulting
from unidentified infectious agents.

Malabsorption in Sprue.

❖ In the early stages of sprue, intestinal absorption of fat is more impaired than absorption
of other digestive products.
❖ The fat that appears in the stools is almost entirely in the form of salts of fatty acids
rather than undigested fat, demonstrating that the problem is one of absorption, not of
digestion.
❖ In fact, the condition is frequently called steatorrhea, which means simply excess fats in
the stools.
❖ In very severe cases of sprue, in addition to malabsorption of fats there is also impaired
absorption of proteins, carbohydrates, calcium, vitamin K, folic acid, and vitamin B12.
❖ As a result, the person suffers (1) severe nutritional deficiency, often developing wasting
of the body; (2) osteomalacia (demineralization of the bones because of lack of calcium);
(3) inadequate blood coagulation caused by lack of vitamin K; and (4) macrocytic anemia
of the pernicious anemia type, owing to diminished vitamin B12 and folic acid absorption.
 Plasma proteins

„ INTRODUCTION
Plasma proteins are:
1. Serum albumin
2. Serum globulin
3. Fibrinogen.
Serum contains only albumin and globulin. Fibrinogen is absent in serum because, it is
converted into fibrin during blood clotting. Because of this, the albumin and globulin are usually
called serum albumin and serum globulin.

„ NORMAL VALUES
Normal values of the plasma proteins are:
Total proteins : 7.3 g/dL (6.4 to 8.3 g/dL)
Serum albumin : 4.7 g/dL
Serum globulin : 2.3 g/dL
Fibrinogen : 0.3 g/dL

„ PROPERTIES OF PLASMA PROTEINS

„ MOLECULAR WEIGHT
Albumin : 69,000
Globulin : 1,56,000
Fibrinogen : 4,00,000
Thus, the molecular weight of fibrinogen is greater than that of other two proteins.

„ ONCOTIC PRESSURE Plasma proteins are responsible for the oncotic or osmotic pressure in
the blood. Osmotic pressure exerted by proteins in the plasma is called colloidal osmotic
(oncotic) pressure (Chapter 3). Normally, it is about 25 mm Hg. Albumin plays a major role in
exerting oncotic pressure.

„ SPECIFIC GRAVITY
Specific gravity of the plasma proteins is 1.026.

„ BUFFER ACTION
Acceptance of hydrogen ions is called buffer action. The plasma proteins have 1/6 of total
buffering action of the blood.

„ ORIGIN OF PLASMA PROTEINS

„ IN EMBRYO
In embryonic stage, the plasma proteins are synthesized by the mesenchyme cells. The
albumin is synthesized first and other proteins are synthesized later.
„ IN ADULTS
In adults, the plasma proteins are synthesized mainly from reticuloendothelial cells of liver. The
plasma proteins are synthesized also from spleen, bone marrow, disintegrating blood cells and
general tissue cells. Gamma globulin is synthesized from B lymphocytes.

„ FUNCTIONS OF PLASMA PROTEINS

Plasma proteins are very essential for the body. Following are the functions of plasma proteins:
„ 1. ROLE IN COAGULATION OF BLOOD
Fibrinogen is essential for the coagulation of blood.

„ 2. ROLE IN DEFENSE MECHANISM OF BODY Gamma globulins play an important role in

the defense mechanism of the body by acting as antibodies (immune substances). These
proteins are also called immunoglobulins. Antibodies react with antigens of various
microorganisms, which cause diseases like diphtheria, typhoid, streptococcal infections,
mumps, influenza, measles, hepatitis, rubella, polio myelitis, etc.

„ 3. ROLE IN TRANSPORT MECHANISM

Plasma proteins are essential for the transport of various substances in the blood. Albumin,
alpha globulin and beta globulin are responsible for the transport of the hormones, enzymes,
etc. The alpha and beta globulins play an important role in the transport of metals in the blood.

„ 4. ROLE IN MAINTENANCE OF OSMOTIC PRESSURE IN BLOOD

At the capillary level, most of the substances are exchanged between the blood and the tissues.
However, because of their large size, the plasma proteins cannot pass through the capillary
membrane easily and remain in the blood. In the blood, these proteins exert the colloidal
osmotic (oncotic) pressure. Osmotic pressure exerted by the plasma proteins is about 25 mm
Hg. Since the concentration of albumin is more than the other plasma proteins, it exerts
maximum pressure. Globulin is the next and fibrinogen exerts least pressure.
 LIPOPROTEINS

Because lipids, such as cholesterol and triglycerides, are insoluble in water these lipids must be
transported in association with proteins (lipoproteins) in the circulation. Large quantities of fatty
acids from meals must be transported as triglycerides to avoid toxicity. These lipoproteins play a
key role in the absorption and transport of dietary lipids by the small intestine, in the transport of
lipids from the liver to peripheral tissues, and the transport of lipids from peripheral tissues to the
liver and intestine (reverse cholesterol transport). A secondary function is to transport toxic
foreign hydrophobic and amphipathic compounds, such as bacterial endotoxin, from areas of
invasion and infection (1).
Go to:

STRUCTURE OF LIPOPROTEINS (2)

Lipoproteins are complex particles that have a central hydrophobic core of non-polar lipids,
primarily cholesterol esters and triglycerides. This hydrophobic core is surrounded by a
hydrophilic membrane consisting of phospholipids, free cholesterol, and apolipoproteins. Plasma
lipoproteins are divided into seven classes based on size, lipid composition, and apolipoproteins.

Chylomicrons
These are large triglyceride rich particles made by the intestine, which are involved in the
transport of dietary triglycerides and cholesterol to peripheral tissues and liver. These particles
contain apolipoproteins A-I, A-II, A-IV, A-V, B-48, C-II, C-III, and E. Apo B-48 is the core
structural protein and each chylomicron particle contains one Apo B-48 molecule. The size of
chylomicrons varies depending on the amount of fat ingested. A high fat meal leads to the
formation of large chylomicron particles due to the increased amount of triglyceride being
transported whereas in the fasting state the chylomicron particles are small carrying decreased
quantities of triglyceride.

Chylomicron Remnants
The removal of triglyceride from chylomicrons by peripheral tissues results in smaller particles
called chylomicron remnants. Compared to chylomicrons these particles are enriched in
cholesterol and are pro-atherogenic.

Very Low-Density Lipoproteins (VLDL)

These particles are produced by the liver and are triglyceride rich. They contain apolipoprotein
B-100, C-I, C-II, C-III, and E. Apo B-100 is the core structural protein and each VLDL particle
contains one Apo B-100 molecule. Similar to chylomicrons the size of the VLDL particles can
vary depending on the quantity of triglyceride carried in the particle. When triglyceride
production in the liver is increased, the secreted VLDL particles are large. However, VLDL
particles are smaller than chylomicrons.

Intermediate-Density Lipoproteins (IDL; VLDL Remnants)

The removal of triglycerides from VLDL by muscle and adipose tissue results in the formation
of IDL particles which are enriched in cholesterol. These particles contain apolipoprotein B-100
and E. These IDL particles are pro-atherogenic.

Low-Density Lipoproteins (LDL)

These particles are derived from VLDL and IDL particles and they are even further enriched in
cholesterol. LDL carries the majority of the cholesterol that is in the circulation. The
predominant apolipoprotein is B-100 and each LDL particle contains one Apo B-100 molecule.
LDL consists of a spectrum of particles varying in size and density. An abundance of small dense
LDL particles are seen in association with hypertriglyceridemia, low HDL levels, obesity, type 2
diabetes (i.e. patients with the metabolic syndrome) and infectious and inflammatory states.
These small dense LDL particles are considered to be more pro-atherogenic than large LDL
particles for a number of reasons. Small dense LDL particles have a decreased affinity for the
LDL receptor resulting in a prolonged retention time in the circulation. Additionally, they more
easily enter the arterial wall and bind more avidly to intra-arterial proteoglycans, which traps
them in the arterial wall. Finally, small dense LDL particles are more susceptible to oxidation,
which could result in an enhanced uptake by macrophages.

High-Density Lipoproteins (HDL)

These particles play an important role in reverse cholesterol transport from peripheral tissues to
the liver, which is one potential mechanism by which HDL may be anti-atherogenic. In addition,
HDL particles have anti-oxidant, anti-inflammatory, anti-thrombotic, and anti-apoptotic
properties, which may also contribute to their ability to inhibit atherosclerosis. HDL particles are
enriched in cholesterol and phospholipids. Apolipoproteins A-I, A-II, A-IV, C-I, C-II, C-III, and
E are associated with these particles. Apo A-I is the core structural protein and each HDL
particle may contain multiple Apo A-I molecules. HDL particles are very heterogeneous and can
be classified based on density, size, charge, or apolipoprotein composition

Lipoprotein (a) (Lp (a))

Lp (a) is an LDL particle that has apolipoprotein (a) attached to Apo B-100 via a disulfide bond.
This particle is pro-atherogenic. The physiologic function of this lipoprotein is unknown.
Go to:

APOLIPOPROTEINS (3,4)
Apolipoproteins have four major functions including 1) serving a structural role, 2) acting as
ligands for lipoprotein receptors, 3) guiding the formation of lipoproteins, and 4) serving as
activators or inhibitors of enzymes involved in the metabolism of lipoproteins (Table 3).
Apolipoproteins thus play a crucial role in lipoprotein metabolism.

Apolipoprotein A-I
Apo A-I is synthesized in the liver and intestine and is the major structural protein of HDL
accounting for approximately 70% of HDL protein. It also plays a role in the interaction of HDL
with ATP-binding cassette protein A1 (ABCA1), ABCG1, and class B, type I scavenger receptor
(SR-B1). Apo A-I is an activator of lecithin: cholesterol acyltransferase (LCAT), an enzyme that
converts free cholesterol into cholesteryl ester. High levels of Apo A-I is associated with a
decreased risk of atherosclerosis.

Apolipoprotein A-II
Apo A-II is synthesized in the liver and is the second most abundant protein on HDL accounting
for approximately 20% of HDL protein. The role of Apo A-II in lipid metabolism is unclear. Apo
A-II is a strong predictor of risk for CVD.

Apolipoprotein A-IV (5)

Apo A-IV is synthesized in the intestine during fat absorption. Apo A-IV is associated with
chylomicrons and high-density lipoproteins, but is also found in the lipoprotein-free fraction. Its
precise role in lipoprotein metabolism remains to be determined but studies have suggested a role
for Apo A-IV in regulating food intake.

Apolipoprotein A-V (6)

Apo A-V is synthesized in the liver and associates with triglyceride rich lipoproteins. It is an
activator of LPL mediated lipolysis and thereby plays an important role in the metabolism of
triglyceride rich lipoproteins.

Apolipoprotein B-48
Apo B-48 is synthesized in the intestine and is the major structural protein of chylomicrons and
chylomicron remnants. There is a single molecule of apo B-48 per chylomicron particle. There is
a single apolipoprotein B gene that is expressed in both the liver and intestine. The intestine
expresses a protein that is approximately ½ the size of the liver due to mRNA editing. The
apobec-1 editing complex is expressed in the intestine and edits a specific cytidine to an uracil in
the apo B mRNA in the intestine creating a stop codon that results in the cessation of protein
translation and a shorter Apo B (Apo B-48). Notably Apo B-48 is not recognized by the LDL
receptor.

Apolipoprotein B-100
Apo B-100 is synthesized in the liver and is the major structural component of VLDL, IDL, and
LDL. There is a single molecule of Apo B-100 per VLDL, IDL, and LDL particle. Apo B-100 is
a ligand for the LDL receptor and therefore plays an important role in the clearance of
lipoprotein particles. High levels of Apo B-100 is associated with an increased risk of
atherosclerosis.

Apolipoprotein C (7,8)
The C apolipoproteins are synthesized primarily in the liver and freely exchange between
lipoprotein particles and therefore are found in association with chylomicrons, VLDL, and HDL.
Apo C-II is a co-factor for lipoprotein lipase (LPL) and thus stimulates triglyceride hydrolysis
(7). Loss of function mutations in Apo C-II result in marked hypertriglyceridemia due to a failure
to metabolize triglyceride rich lipoproteins.
Apo C-III is an inhibitor of LPL (9). Additionally, Apo C-III inhibits the interaction of
triglyceride rich lipoproteins with their receptors. Recent studies have shown that loss of function
mutations in Apo C-III lead to decreases in serum triglyceride levels and a reduced risk of
cardiovascular disease. Interestingly, inhibition of Apo C-III expression results in a decrease in
serum triglyceride levels even in patients deficient in lipoprotein lipase indicating that the ability
of Apo C-III to modulate serum triglyceride levels is not dependent solely on regulating
lipoprotein lipase activity.

Apolipoprotein E (10)
Apolipoprotein E is synthesized in many tissues but the liver and intestine are the primary source
of circulating Apo E. Apo E exchanges between lipoprotein particles and is associated with
chylomicrons, chylomicron remnants, VLDL, IDL, and a subgroup of HDL particles. There are
three common genetic variants of Apo E (Apo E2, E3, and E4). ApoE2 differs from the most
common isoform, Apo E3, by a single amino acid substitution where cysteine substitutes for
arginine at residue 158. Apo E4 differs from Apo E3 at residue 112, where arginine substitutes
for cysteine. Apo E3 and E4 are ligands for the LDL receptor while Apo E2 is poorly recognized
by the LDL receptor. Patients who are homozygous for Apo E2 can develop familial
dysbetalipoproteinemia. Apo E4 is associated with an increased risk of Alzheimer’s disease and
an increased risk of atherosclerosis.

Apolipoprotein (a) (11)

Apo (a) is synthesized in the liver. This protein is a homolog of plasminogen and its molecular
weight varies from 300,000 to 800,000. It is attached to Apo B-100 via a disulfide bond. High
levels of Apo (a) are associated with an increased risk of atherosclerosis. Apo (a) is an inhibitor
of fibrinolysis and can also enhance the uptake of lipoproteins by macrophages, both of which
could increase the risk of atherosclerosis. The physiologic function of Apo (a) is unknown.
Interestingly this apolipoprotein is found in primates but not in other species.
 Erythropoiesis
Haematopoeisis describes the production of cells that circulate in the
bloodstream. Specifically, erythropoiesis is the process by which red blood cells
(erythrocytes) are produced.

On average, the body produces an astounding 2.5 billion red cells/kg/day.

Erythrocytes arise from a complex line of cells, and their rate of production is
tightly regulated to ensure adequate but not excessive numbers of red blood cells
are produced.

In this article, we will consider the stages and regulation of erythropoiesis, and
review what happens when it goes wrong.
Sites of Erythropoiesis
The site of erythropoiesis changes throughout life. In the very early foetus, it
occurs in the yolk sac. From 2 – 5 months’ gestation it occurs in the liver and
spleen before finally establishing in the bone marrow from about 5 months’
gestation.

In children, erythropoiesis can occur in the bone marrow of most bones. However,
in adults, it only occurs in the bone marrow of the vertebrae, ribs, sternum,
sacrum, pelvis and proximal femur.

When erythropoiesis is inadequate in the bone marrow, this can trigger

extramedullary haematopoiesis – i.e. haematopoiesis occurring outside the
marrow. This is commonly seen in haemoglobulinopathies such as thalassaemias
and myelofibrosis.
Stages of Erythropoiesis
The production of all blood cells begins with the haemocytoblast, a multipotent
haematopoietic stem cell. Haemocytoblasts have the greatest powers of
self-renewal of any adult cell. They are found in the bone marrow and can be
mobilised into the circulating blood when needed.

Some haemocytoblasts differentiate into common myeloid progenitor cells, which

go on to produce erythrocytes, as well as mast cells, megakaryocytes and
myeloblasts.
By Mikael Häggström [CC BY-SA 3.0] via Wikimedia Commons

Fig 1 – The cell line of erythropoeisis

The process by which common myeloid progenitor cells become fully mature red
blood cells involves several stages. First, they become normoblasts (aka
eryhthroblasts), which are normally present in the bone marrow only.

Then, they lose their nucleus as they mature into reticulocytes, which can be
thought of as immature red blood cells. Some of these are released into the
peripheral circulation.

Finally, reticulocytes lose their remaining organelles as they mature into

erythrocytes-which are fully mature red blood cells. the average lifespan of a red
blood cell is approximately 120 days.

During this maturation process, there is nuclear extrusion – i.e. mature

erythrocytes have no nucleus. Nucleated red blood cells present in a sample of
bone marrow can indicates the release of incompletely developed cells. This can
occur in pathology such as thalassaemia, severe anaemia or haematological
malignancy.

Liu et al., Transdifferentiation of Human Hair Follicle Mesenchymal Stem Cells

into Red Blood Cells by OCT4. Stem Cell Int. Feb 2015.

Figure 2 – Maturation into an erythrocyte.

Regulation of Erythropoiesis
Erythropoiesis is driven mainly by the hormone erythropoietin (EPO), which is a
glycoprotein cytokine.

EPO is secreted by the kidney. It is constantly secreted at a low level, sufficient for
the normal regulation of erythropoiesis. However, if the erythrocyte level becomes
inadequate, the blood becomes relatively hypoxic. When there is a reduced partial
pressure of oxygen (pO2) in the kidney, this is detected by the renal interstitial
peritubular cells.

In response, there is a surge in EPO production, which acts on the bone marrow
to stimulate increased red blood cell production. This causes haemoglobin levels
to increase, subsequently causing the pO2 to rise and therefore EPO levels to fall.
The feedback loop is complete.
 ABNORMALITIES IN BLOOD FORMATION

Blood disorders involve problems in your blood or bone marrow, the

fatty area inside your bones that produces new red blood cells, white
blood cells, and platelets. When something goes wrong with any of these
cell types or with the clotting factors in the plasma (the liquid part of the
blood), you may be diagnosed with a blood disorder. The most common
types are anemia, bleeding disorders such as hemophilia, and blood

clots.1

In general, when physicians refer to something as a blood disorder, they

are implying that the condition is not cancerous (i.e., leukemia or
lymphoma).

Types and Causes

Blood disorders can be inherited or acquired. Sometimes you develop a
blood disorder due to an infection, toxic exposure, drug side effect, or
lack of certain nutrients in your diet (such as iron, vitamin K, or vitamin

B12).2

Blood disorders are defined by changes in any of the parts of your blood:

​ White blood cells, which help fight infections: They include

neutrophils, lymphocytes, monocytes, eosinophils, and basophils.
​ Red blood cells, which carry oxygen to tissues
​ Platelets, which help stop bleeding
 ​ Plasma, which carries various components including procoagulant
factors (that help stop bleeding) and anticoagulant factors (that
prevent clot formation)

Following are common blood disorders:

​ Neutropenia is a decreased number of neutrophils, a type of white

blood cell. The neutrophils are an important part of your immune
system that help fight off bacterial infections. The most common
cause of neutropenia is chemotherapy given to treat cancer. Other
causes include autoimmune neutropenia, Shwachman-Diamond
syndrome, and cyclic neutropenia.3
​ Anemia results from a decreased number of red blood cells or
hemoglobin—the protein that carries oxygen. Anemia can result
from iron deficiency, sickle cell disease, or thalassemia, as well as a
number of other conditions and diseases.4
​ Polycythemia vera (PV) is a condition in which your bone marrow
makes an excessive number of red blood cells. This increase can
elevate your risk of clot formation.5
​ Immune thrombocytopenic purpura (ITP) is a condition in which
your platelets are marked as “foreign” and are, therefore,
destroyed. This can lead to very low platelet counts and bleeding.6
​ Thrombocytosis refers to an increased number of platelets.
Fortunately, most of the time, elevated platelet counts are caused
by something else (reactive thrombocytosis) and will get better
when the underlying condition improves. More concerning,
however, are blood conditions like essential thrombocythemia
(ET), where your bone marrow makes an extremely high number of
platelets, increasing the risk of developing a blood clot, and
sometimes bleeding.7
​ Hemophilia is an inherited condition that results in decreased
amounts of procoagulant factors (specifically, 8, 9, and 11). This
 results in easy bleeding. People with hemophilia are sometimes
referred to as “free bleeders.”
​ Blood clots (thrombosis) can occur anywhere in the body. In the
brain, it is called a stroke; in the heart, it is called a heart attack (or
myocardial infarction). Deep vein thrombosis (DVT) commonly
refers to blood clots in the arms or legs.

Some blood disorders live in a space between benign and malignant

(cancerous)—sometimes referred to as premalignant—and may evolve
into cancer. Leukemia is generally not included in the broader term of

blood disorders as it is a cancer of the blood/bone marrow.8

Symptoms
Symptoms of blood disorders vary widely depending on which blood
component is affected. Some blood disorders cause few symptoms, while
others are responsible for more.

For example:

​ Anemia (low red blood cells) can cause fatigue, shortness of

breath, or increased heart rate.
​ Thrombocytopenia (low platelets) can cause increased bruising or
bleeding from the mouth or nose.8
​ Hemophilia (poor clotting) can also cause increased bleeding but
is known to specifically target muscles and joints without
significant injury.8
​ Blood clots (inappropriate clotting) in the arms or legs may cause
swelling and pain.8
​
Diagnosis
Blood disorders are predominantly seen by hematologists—physicians
who specialize in the diagnosis and treatment of problems in your blood
and/or bone marrow.

Your physician will examine you and your symptoms to determine the
most likely diagnosis. Most of the time blood work is needed. Sometimes
blood disorders are found on lab work drawn for other reasons like an
annual physical exam.

The most commonly used test to diagnose blood disorders is the

complete blood count (CBC).9 The CBC looks at the three types of blood

cells and determines if any are increased or decreased or if more than

one blood cell is affected. A blood smear may also be included with the
CBC, with a microscopic examination to provide additional helpful
information.

For bleeding or clotting problems, your physician will likely order

coagulation blood tests, which include the prothrombin time (PT) and
the partial thromboplastin time (PTT). If the PT or PTT is prolonged
(indicating that you are more likely to bleed than other people), further
evaluation is needed. Your physician may order levels of individual
coagulation factors or assess the function of your platelets.

Blood clots are a little different. To diagnose them, your physician will
need to image the concerning area. In the arms or legs, an ultrasound is
used to assess for possible clots. In the lungs or brain, computerized
tomography (CT) or magnetic resonance imaging (MRI) scans are
commonly used.

A bone marrow biopsy may be needed in some cases to help make a

diagnosis. This is usually done by aspirating marrow from the hip.

Treatment
Treatment is determined by your specific diagnosis. Some chronic blood
disorders have no specific treatment but may require treatment during
acute events. For example:

​ Anemia caused by iron deficiency will be treated with iron

supplementation. Beta thalassemia major, an inherited form of
anemia, is treated with monthly blood transfusions.10
​ Hemophilia can be treated with coagulation factor replacement
products that can be used to treat individual bleeds or, when given
on a regular basis, prevent bleeds (prophylaxis).11
​ Polycythemia vera is treated by phlebotomy—drawing a pint of
blood intermittently to keep the number of red cells from dropping
below the dangerous level.
​ Blood clots may be treated with anticoagulant therapy (blood
thinners). Some cases may require catheter-directed thrombolysis
to dissolve the blockage.
​ Thrombocythemia may be treated with aspirin or might require
medications such as hydroxyurea, interferon alfa, or anagrelide
(rarely used).
​ Immune thrombocytopenia might be treated with corticosteroids
such as prednisone or medications that raise the platelet count.
Removing the spleen is another treatment performed when needed.
 Anemia

Overview
Anemia is a condition in which you lack enough healthy red blood cells to carry
adequate oxygen to your body's tissues. Having anemia, also referred to as low
hemoglobin, can make you feel tired and weak.

There are many forms of anemia, each with its own cause. Anemia can be temporary or
long term and can range from mild to severe. In most cases, anemia has more than one
cause. See your doctor if you suspect that you have anemia. It can be a warning sign of
serious illness.

Treatments for anemia, which depend on the cause, range from taking supplements to
having medical procedures. You might be able to prevent some types of anemia by
eating a healthy, varied diet.

Types
1. Aplastic anemia
2. Iron deficiency anemia
3. Sickle cell anemia
4. Thalassemia
5. Vitamin deficiency anemia

Symptoms
Anemia signs and symptoms vary depending on the cause and severity of anemia.
Depending on the causes of your anemia, you might have no symptoms.

Signs and symptoms, if they do occur, might include:

 ● Fatigue
● Weakness
● Pale or yellowish skin
● Irregular heartbeats
● Shortness of breath
● Dizziness or lightheadedness
● Chest pain
● Cold hands and feet
● Headaches

At first, anemia can be so mild that you don't notice it. But symptoms worsen as anemia
worsens.

Causes

Anemia can be due to a condition present at birth (congenital) or to a condition you

develop (acquired). Anemia occurs when your blood doesn't have enough red blood
cells.

This can happen if:

● Your body doesn't make enough red blood cells

● Bleeding causes you to lose red blood cells more quickly than they can be
replaced
● Your body destroys red blood cells

What red blood cells do

Your body makes three types of blood cells — white blood cells to fight infection,
platelets to help your blood clot, and red blood cells to carry oxygen from your lungs to
the rest of your body and carbon dioxide from the body back to the lungs.
Red blood cells contain hemoglobin — an iron-rich protein that gives blood its red color.
Hemoglobin enables red blood cells to carry oxygen from your lungs to all parts of your
body and to carry carbon dioxide from other parts of the body to your lungs to be
exhaled.

Most blood cells, including red blood cells, are produced regularly in your bone marrow
— a spongy material found within the cavities of many of your large bones. To produce
hemoglobin and red blood cells, your body needs iron, vitamin B-12, folate and other
nutrients from the foods you eat.

Causes of anemia

Different types of anemia have different causes. They include:

● Iron deficiency anemia. This most common type of anemia is caused by a

shortage of iron in your body. Your bone marrow needs iron to make
hemoglobin. Without adequate iron, your body can't produce enough
hemoglobin for red blood cells.
Without iron supplementation, this type of anemia occurs in many pregnant
women. It's also caused by blood loss, such as from heavy menstrual
bleeding; an ulcer in the stomach or small bowel; cancer of the large bowel;
and regular use of some pain relievers that are available without a
prescription, especially aspirin, which can cause inflammation of the
stomach lining resulting in blood loss. It's important to determine the source
of iron deficiency to prevent recurrence of the anemia.
● Vitamin deficiency anemia. Besides iron, your body needs folate and
vitamin B-12 to produce enough healthy red blood cells. A diet lacking in
these and other key nutrients can cause decreased red blood cell
production. Some people who consume enough B-12 aren't able to absorb
the vitamin. This can lead to vitamin deficiency anemia, also known as
pernicious anemia.
● Anemia of inflammation. Certain diseases — such as cancer, HIV/AIDS,
rheumatoid arthritis, kidney disease, Crohn's disease and other acute or
 chronic inflammatory diseases — can interfere with the production of red
blood cells.
● Aplastic anemia. This rare, life-threatening anemia occurs when your body
doesn't produce enough red blood cells. Causes of aplastic anemia include
infections, certain medicines, autoimmune diseases and exposure to toxic
chemicals.
● Anemias associated with bone marrow disease. A variety of diseases,
such as leukemia and myelofibrosis, can cause anemia by affecting blood
production in your bone marrow. The effects of these types of cancer and
cancer-like disorders vary from mild to life-threatening.
● Hemolytic anemias. This group of anemias develops when red blood cells
are destroyed faster than bone marrow can replace them. Certain blood
diseases increase red blood cell destruction. You can inherit a hemolytic
anemia, or you can develop it later in life.
● Sickle cell anemia. This inherited and sometimes serious condition is a
hemolytic anemia. It's caused by a defective form of hemoglobin that forces
red blood cells to assume an abnormal crescent (sickle) shape. These
irregular blood cells die prematurely, resulting in a chronic shortage of red
blood cells.

Risk factors

These factors place you at increased risk of anemia:

● A diet lacking in certain vitamins and minerals. A diet consistently low in

iron, vitamin B-12, folate and copper increases your risk of anemia.
● Intestinal disorders. Having an intestinal disorder that affects the
absorption of nutrients in your small intestine — such as Crohn's disease
and celiac disease — puts you at risk of anemia.
● Menstruation. In general, women who haven't had menopause have a
greater risk of iron deficiency anemia than do men and postmenopausal
women. Menstruation causes the loss of red blood cells.
 ● Pregnancy. Being pregnant and not taking a multivitamin with folic acid and
iron, increases your risk of anemia.
● Chronic conditions. If you have cancer, kidney failure or another chronic
condition, you could be at risk of anemia of chronic disease. These
conditions can lead to a shortage of red blood cells.
Slow, chronic blood loss from an ulcer or other source within your body can
deplete your body's store of iron, leading to iron deficiency anemia.
● Family history. If your family has a history of an inherited anemia, such as
sickle cell anemia, you also might be at increased risk of the condition.
● Other factors. A history of certain infections, blood diseases and
autoimmune disorders increases your risk of anemia. Alcoholism, exposure
to toxic chemicals and the use of some medications can affect red blood cell
production and lead to anemia.
● Age. People over age 65 are at increased risk of anemia.

Complications

Left untreated, anemia can cause many health problems, such as:

● Extreme fatigue. Severe anemia can make you so tired that you can't
complete everyday tasks.
● Pregnancy complications. Pregnant women with folate deficiency anemia
can be more likely to have complications, such as premature birth.
● Heart problems. Anemia can lead to a rapid or irregular heartbeat
(arrhythmia). When you're anemic your heart pumps more blood to make up
for the lack of oxygen in the blood. This can lead to an enlarged heart or
heart failure.
● Death. Some inherited anemias, such as sickle cell anemia, can lead to
life-threatening complications. Losing a lot of blood quickly results in acute,
severe anemia and can be fatal. Among older people, anemia is associated
with an increased risk of death.

Prevention
Many types of anemia can't be prevented. But you can avoid iron deficiency anemia and
vitamin deficiency anemias by eating a diet that includes a variety of vitamins and
minerals, including:

● Iron. Iron-rich foods include beef and other meats, beans, lentils,
iron-fortified cereals, dark green leafy vegetables and dried fruit.
● Folate. This nutrient, and its synthetic form folic acid, can be found in fruits
and fruit juices, dark green leafy vegetables, green peas, kidney beans,
peanuts, and enriched grain products, such as bread, cereal, pasta and rice.
● Vitamin B-12. Foods rich in vitamin B-12 include meat, dairy products, and
fortified cereal and soy products.
● Vitamin C. Foods rich in vitamin C include citrus fruits and juices, peppers,
broccoli, tomatoes, melons and strawberries. These also help increase iron
absorption.

If you're concerned about getting enough vitamins and minerals from food, ask your
doctor whether a multivitamin might help.

Hemoglobinopathies

Hemoglobinopathies are among the most common inherited diseases around

the world. They have become much more common recently in northern and
central Europe, including Germany, due to immigration.

The hemoglobinopathies encompass all genetic diseases of hemoglobin. They

fall into two main groups: thalassemia syndromes and structural hemoglobin
variants (abnormal hemoglobins). α- and β-thalassemia are the main types of
thalassemia; the main structural hemoglobin variants are HbS, HbE and HbC.
The main Hb abnormalities, both worldwide and among immigrants living in
Germany, are HbS, HbC, and HbE. The large groups of rare Hb abnormalities
that occur only in isolated cases all over the world should also be monitored.
These are often accompanied by hemolysis, polycythemia, and/or cyanosis.
Identifying these is an important part of differential diagnosis of
hematological diseases where other efforts towards diagnosis have proved
inconclusive.

HbS and sickle-cell disease

The term “sickle-cell disease” includes all manifestations of abnormal HbS

levels (proportion of HbS >50%). These include homozygous sickle-cell
disease (HbSS) and a range of mixed heterozygous hemoglobinopathies
(HbS/β-thalassemia, HbSC disease, and other combinations).

According to the International Nomenclature, the previously commonly-used

term “sickle-cell anemia” should not be used, as the dominant aspects of the
disease are vascular obliterations and the organ damage they cause, not
anemia.
HbS is the most dangerous of all hemoglobinopathies. The sickle cells caused
by a lack of oxygen lead to vascular obliterations, so infarctions with tissue
death can occur in almost all organs (skin, liver, spleen, bone, kidneys, retina,
CNS). Chronic hemolytic anemia can usually be well tolerated. Aplastic
crises are seen with severe anemia following viral infections.

Diagnostic criteria and cardinal symptoms: Symptoms begin before the

age of one, with chronic hemolytic anemia and developmental disorders. The
main problems are pain crises (sickle-cell crises) that can affect the back,
extremities, thorax, abdomen, and CNS in particular. Patients are also
dangerously susceptible to infection, particularly by pneumococci,
hemophilus, salmonellae, klebsiellae, and mycoplasmae. Sepsis,
osteomyelitis, and meningeal events, sometimes with cardiac involvement,
frequently result in death. Spleen crises, acute thoracic syndrome (ATS), and
strokes are also fatal in more than a few cases. These issues cause serious
organ damage.

Optimally treated patients can have a projected life span of 50 to 60 years.

Heterozygous HbS gene carriers are not affected clinically or

hematologically.
HbC abnormality and HbC disease

HbC homozygosity, or HbC disease, progresses in a similar way to sickle-cell

disease, but is less serious. Variable hemolytic anemia is the most dominant
form. Heterozygous HbC gene carriers enjoy complete clinical health.

HbE abnormality and HbE disease

HbE is an extremely common Hb variant native to South-East Asia. Its

disease pattern is similar to that of β-thalassemias. Hb is also unstable, which
means that hemolysis can be caused by viral infections and medications. HbE
is often combined with thalassemias, which may result in serious major-form
hemoglobinopathies.

HbE homozygosity (HbE disease): Typically, this is moderate, microcytic

hypochromic anemia with possible hemolysis due to exogenous causes.
HbE heterozygosity: Patients have variable hypochromic anemia similar to
that found in β-thalassemia minor.

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Treatment for β-thalassemias

β-thalassemia major

After being diagnosed, patients should be referred to a hematology center for

counseling and to decide on treatment, and, if appropriate, for regular
diagnosis appraisal.

The current international standard treatment is based on the results of studies

conducted at large sites in England and the USA and is stated in available
child and adolescent medicine guidelines (AWMF/II/025–017.htm).
Curative treatment: Hematopoietic stem-cell transplantation is the first-line
treatment if a donor can be found.

Supportive treatment: Supportive treatment for thalassemia major includes

lifelong regular transfusions combined with effective iron removal.
Hemosiderosis-related organ damage requires specific treatment .

● Transfusion therapy: Repeat hemoglobin concentration levels of less

than 8 g/dL are an indication for beginning transfusion therapy. The
target baseline hemoglobin level is 9 to 10.5 g/dL. The recommended
frequency of transfusions is usually one every three weeks. Transfusion
volume is usually 12 to 14 mg/kg body weight (BW) with an RBC
concentrate hematocrit of 60%. Target Hb levels are 13 to 13.5 g/dL.
● Drug treatment to remove iron (chelation therapy): Iron removal is
indicated when serum ferritin concentration repeatedly exceeds 1000
ng/mL.
● Iron removal using deferoxamine: Standard deferoxamine
treatment is a daily subcutaneous infusion (over several hours) at
a dose of – 40 – (50) mg/kg BW, 5 to 7 days per week. Dose
adjustment is based on monthly testing of serum ferritin
concentration. Patients must be closely monitored for potential
 side effects of deferoxamine (reduced growth, bone damage,
high-frequency hearing loss, retinal damage).
● Iron removal with deferasirox: Deferasirox is a well-tolerated
iron chelator in tablet form and has taken on a central role in iron
removal therapy. However, this is a relatively new drug of which
no long-term studies have been conducted. A standard dose of 20
mg/kg BW/day is recommended for patients with β-thalassemia
major who are receiving long-term transfusion therapy. This dose
must be adjusted on the basis of monthly measuring of ferritin
levels. The main side effects (close monitoring required!) are
kidney failure, agranulocytosis, and liver failure. Liver iron levels
must be measured every two years.
● Splenectomy is indicated for tumorous enlargement of the spleen with
increased need for transfusions and hypersplenism.

β-thalassemia intermedia

Transfusion therapy is indicated for patients with complications as a result of

major increases in erythropoiesis, and patients with anemia and an inability to
maintain stable hemoglobin levels of more than 8 g/dL. In such cases,
lifelong continuous transfusion therapy should be considered, rather than
transfusions at intervals, combined with appropriate chelation therapy.
β-thalassemia minor

For severe anemia, folic acid supplements (0.5 mg/day orally) may be
considered. Iron supplements are contraindicated unless there is simultaneous
iron deficiency.

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Treatment for α-thalassemias

α-thalassemia minima and minor do not require treatment. Iron supplements

are contraindicated (except in cases of iron deficiency).

Treatment for HbH disease depends on the severity of the clinical picture,
which can vary widely. Transfusions are rarely indicated. Anemia requires
regular substitution with folic acid (e.g. 5 mg/week). Iron supplements are
contraindicated (unless there is simultaneous iron deficiency).

For Hb Bart’s syndrome, transfusions are required in utero and continuously

after birth. Where possible, stem-cell transplantation is performed.
 Go to:

Treatment for sickle-cell disease

Following diagnosis, patients should be referred to a hematology center for

counseling and to decide on treatment, and, if appropriate, for regular
diagnosis appraisal. The current standard treatment is based on the results of
studies conducted at large sites in England and the USA and is stated in
available guidelines.

Cerebral Spinal Fluid

Cerebrospinal fluid (CSF) is an ultrafiltrate of plasma contained within the ventricles of the brain
and the subarachnoid spaces of the cranium and spine. It performs vital functions, including
providing nourishment, waste removal, and protection to the brain. Adult CSF volume is
estimated to be 150 ml, with a distribution of 125 ml within the subarachnoid spaces and 25 ml
within the ventricles. CSF is predominantly secreted by the choroid plexus with other sources
playing a more poorly defined role. In the adult population, its secretion varies between
individuals, usually ranging from 400 to 600 ml per day. The constant secretion of CSF
contributes to complete CSF renewal four to five times per 24-hour period in the average young
adult.

When compared to plasma, CSF has a higher concentration of sodium, chloride, and magnesium,
but a lower concentration of potassium and calcium. Unlike plasma, CSF has only trace amounts
of cells, protein, and immunoglobulins. No cells can pass through the blood-CSF barrier,
although small numbers of white blood cells are usually introduced to the CSF indirectly.
Function
CSF assists the brain by providing protection, nourishment, and waste removal. CSF provides
hydromechanical protection of the neuroaxis through two mechanisms. First, CSF acts as a shock
absorber, cushioning the brain against the skull. Second, CSF allows the brain and spinal cord to
become buoyant, reducing the effective weight of the brain from its normal 1,500 grams to a
much lesser 50 grams. The reduction in weight lessens the force applied to the brain parenchyma
and cerebral vessels during mechanical injury. Another function of CSF is to maintain
homeostasis of the interstitial fluid of the brain. A stable environment for brain parenchyma is
imperative for maintaining normal neuronal function.
The major conduit of nutrient supply to the brain is the CP-CSF-ECSB nexus. Substrates needed
by the brain are transported from the blood, through the CP, into the CSF, and then diffuse into
the ECSB for transportation to their sites of action within the brain. CSF also assists in the
removal of brain metabolism waste products, such as peroxidation products, glycosylated
proteins, excess neurotransmitters, debris from the lining of the ventricles, bacteria, viruses, and
otherwise unnecessary molecules.

Mechanism
CSF is continuously secreted with an unchanging composition, functioning to maintain a stable
environment within the brain. CSF is propelled along the neuroaxis from the site of secretion to
the site of absorption, mainly by the rhythmic systolic pulse wave within the choroidal arteries.
Lesser determinants of CSF flow are frequency of respiration, posture, venous pressure of the
jugular vein, the physical effort of the individual, and time of day.

CSF is secreted by the CPs located within the ventricles of the brain, with the two lateral
ventricles being the primary producers. CSF flows throughout the ventricular system
unidirectionally in a rostral to caudal manner. CSF produced in the lateral ventricles travel
through the interventricular foramina to the third ventricle, through the cerebral aqueduct to the
fourth ventricle, and then through the median aperture (also known as the foramen of Magendie)
into the subarachnoid space at the base of the brain. Once in the subarachnoid space, the CSF
begins to have a gentle multidirectional flow that creates an equalization of composition
throughout the CSF. The CSF flows over the surface of the brain and down the length of the
spinal cord while in the subarachnoid space. It leaves the subarachnoid space through arachnoid
villi found along the superior sagittal venous sinus, intracranial venous sinuses, and around the
roots of spinal nerves.
Clinical Significance
Hydrocephalus is a pathological condition in which CSF abnormally accumulates due to
increased CSF production, blockage of flow, or decreased absorption. The ventricles distend to
accommodate elevated CSF volumes, potentially causing damage to the brain by pressing its
tissue against the boney skull. Hydrocephalus may be congenital or acquired. Blocked CSF flow
throughout the ventricles is classified as non-communicating, or obstructive, hydrocephalus. The
blockage is often a mass such as a tumor or an abscess located within a foramen. Because CSF
secretion is constant, obstruction of flow will lead to CSF build up in front of the blockage. For
example, stenosis of the cerebral aqueduct, one of the most common causes of obstructive
hydrocephalus, leads to enlargement of both lateral ventricles as well as the third ventricle. If the
flow of CSF becomes obstructed outside the ventricles, in either the subarachnoid space or site of
absorption, it classifies as communicating, or non-obstructive, hydrocephalus.

CSF Leak is a condition in which CSF is able to escape from the subarachnoid space through a
hole in the surrounding dura. The volume of CSF lost in a leak varies, ranging from minute to
very substantial amounts. If the loss of CSF is great enough, spontaneous intracranial
hypotension (SIH) may occur. SIH most often presents with a positional headache caused by
downward displacement of the brain due to loss of buoyancy previously provided by the CSF.
Posterior neck stiffness, nausea, and vomiting are also common symptoms. The incidence of SIH
is estimated to be 5/100,000 annually. Women are twice as likely to be affected and have a peak
age at around 40 years.

Meningitis is a condition in which the coverings of the brain become inflamed. There are two
classifications of meningitis: aseptic and bacterial. Aseptic meningitis can result from agents
such as fungi, medications, and cancer metastasis, but viruses cause the majority of aseptic
meningitis cases. Fever, nuchal rigidity, and photophobia are classically presenting symptoms.
Diagnosis is via an analysis of CSF obtained through LP. Viral PCR analysis of CSF is helpful in
diagnosing viral meningitis. Treatment is often supportive, controlling fever and pain. Bacterial
meningitis has a much lower incidence than aseptic meningitis, but is more serious. However, the
incidence of bacterial meningitis has substantially dropped due to routine vaccination.

Subarachnoid Hemorrhage (SAH) is the leakage of blood into the subarachnoid space where it
mixes with CSF. Trauma is the most common cause of SAH with 80% of nontraumatic SAHs
resulting from aneurysm rupture. Other nontraumatic causes of SAH include arteriovenous
malformations and vasculitis. Spontaneous SAH has a low incidence, with only 30,000 cases
worldwide annually. Ninety-seven percent of patients with SAH present with a sudden onset
headache, described as a thunderclap headache or the worst headache of the patient's life. Other
symptoms include vomiting, seizures, loss of consciousness, and death. Non-contrast head CT is
useful in diagnosis. CT has high sensitivity after hemorrhage, but sensitivity decreases as time
passes. After a negative CT, an LP should follow to rule out SAH. An LP is positive when
erythrocytes are present in tubes 1 and 4, or xanthochromia is visible. Management of SAH
consists of reducing risks of re-bleeding and avoiding any secondary brain injuries.[11]
Pseudotumor Cerebri Syndrome (PTCS) is a rare medical condition in which intracranial
pressure is raised without the occurrence of ventriculomegaly or intracranial masses. The
pathogenesis is not well understood. The most widely accepted theory proposes decreased
absorption of CSF at the arachnoid granulations or the olfactory lymphatics as the cause. This
condition has an annual incidence rate of 0.9/100,000 in the general population. Before puberty,
both females and males are equally affected, but after puberty, women are affected nine times
more often.Traditional therapy includes medications to decrease CSF secretion from the choroid
plexus. Surgery is indicated for patients with worsening vision caused by papilledema. Surgical
options include optic nerve sheath fenestration and CSF shunting. Most patients with PTCS have
a good outcome, although a small percentage of patients continue to experience persistent
headaches or blindness.