Hyperemesis Gravidarum is a severe form of morning sickness characterized by excessive nausea, vomiting, weight loss and dehydration during pregnancy. It is caused by genetic mutations that lead to overexpression of factors like GDF15 and IGFBP7, stimulating brainstem vomiting centers. High estrogen levels also contribute by relaxing gastrointestinal sphincters and decreasing motility, causing distension that triggers vomiting. The document discusses these physiological mechanisms in detail but has not been fully summarized yet.

1. Hyperemesis
Gravidarum
BY: JERARD LLOYD B. DOMINGO
BSN 2A

2. Hyperemesis Gravidarum
 Is a pregnancy complication characterized by severe nausea,
vomiting, weight loss, and possible dehydration.
 More severe form of morning sickness (emesis gravidarum).
 Symptoms get better after 20th week but may also last the duration
of entire pregnancy.
 HG is characterized by > 3 episodes of vomiting in a day.
 Weight loss, electrolyte disturbances, and dehydration may result.

3. Physiology of Vomiting
Vomiting – forceful expulsion of contents of the stomach
and often proximal intestine.
Vomiting is the last series of 3 events;
1. Nausea – unpleasant feeling and difficult to describe. It is
associated with decreased gastric motility and increased tone
of small intestines. It is triggered when there’s a reverse
peristalsis in small intestines.
2. Retching (“Dry-heaves”) – refers to spasmodic
movements conducted with a closed glottis (opening sa
larynx). The antrum of the stomach contracts and the
fundus and cardiac sphincter relax.

4. Physiology of Vomiting
3. Emesis or Vomition – when gastric and often small intestinal
contents are propelled up to and out of the mouth.
Steps: 3.1. A deep breath is taken, glottis is closed, and larynx is
raised to open the upper esophageal sphincter. Soft palate is
elevated to close off the posterior nares.
3.2. Diaphragm contracts sharply downward to create a negative
pressure in the thorax which facilitates the opening of the
esophagus and distal esophageal sphincter.

5. Physiology of Vomiting
3.3 Simultaneously with downward movement of the diaphragm,
the muscles of the abdominal walls are vigorously contracted,
squeezing the stomach and thus elevating the intra-abdominal
pressure. The pylorus is closed and esophagus is open, the route
route of exit is clear.
*Projectile vomiting – vomits abruptly without pre-monitory
signs. It is caused by gastric outlet obstruction due to foreign
bodies.

6. Control of Vomition
 Brainstem – the vomiting center.
 Bilateral Vomition Centers – in the reticular formation of
medulla oblongata, integrates signals from a large number of
sources. The signal excites and triggers vomition via electrical
stimulation.
1. Visceral Afferents from GI Tract (Vagus or sympathetic
stimulation) – these signals inform the brain of such
conditions such as GI over distention and mucosal irritation.
*GI Over-distention – a very potent stimulus for vomition.

7. Control of Vomition
2. Visceral Afferents from outside GI tract – signals from
bile ducts, peritoneum, heart and a variety of other organs.
These inputs to the vomition centers. (e.g. stone in common
bile duct can result in vomiting.)
3. Afferents from extra-medullary centers in the brain.
Psychic stimuli such as odors and fears, vestibular balance
cranial nerve #8 (motion sickness) and cerebral trauma
result in vomition.
o Chemoreceptor Trigger Zone – is a bilateral set of
centers in the brainstem lying under the floor of the
fourth ventricle. These are chemical receptors that
regulates concentrations in the blood. The receptors of
CTZ is where emetic and anti-emetic drugs act.

8. Control of Vomition
Other stimulus such as anti-emetic/emetic drugs, uremia,
hypoxia and DKA are causing the stimulation of vomition
centers.
• 2 Basic Pathways
1. Neural (visceral, afferents from GI tract, visceral afferents
outside GI tract , and lastly the extra-medullary centers of
brain).
2. Humoral – blood concentration chemical monitoring.
It is important to know how the CTZ was triggered.

9. Risk Factors for Hyperemesis Gravidarum
1. Age
2. Genes
3. Multiple Pregnancy
4. Family history of HG
5. Trophoblastic Disorder
6. UTI
7. Hyperthyroidism

10. 1. Genetic Mutation of GDF15 & IGFBP7
• GDF 15 – Growth Differentiation factor 15.
• Is a family of TGF-β superfamily. It is responsible for cell growth,
differentiation and regulation of body weight. GDF15 encodes placenta,
regulates appetite and feeding behavior.
• It is responsible for cachexia symptoms (nausea, vomiting, weight loss,
anorexia and muscle wasting).
*GFRAL – receptor for GDF15. GDNF Family Receptor Alpha Like. It is found
at the CTZ in the brainstem. It regulates GDF binding, when it is activated, it
regulates the feeding behaviors, nausea and vomiting reflexes.
 GDF15 Mutation/Overexpression – may cause recurrent HG in every
pregnancy. It is overexpressed in the fetal side of the placenta.

11. 1. Genetic Mutation of GDF15 & IGFBP7
• In patients with HG, high levels of GDF 15 are detected.
• There are limited amounts of GFRAL in brainstem, resulting in
overexpression of GDF 15.
• GDF15 + GFRAL = normal regulation of feeding behavior, nausea
and vomiting.
• GFRAL is a brainstem restricted receptor. If GDF15 is
overexpressed, it results in overstimulation of the GDF15-GFRAL
Transduction Pathway, resulting in the overstimulation of
Brainstem Vomition Centers that leads to overstimulation of
vomition. Dysregulation of these factors leads to HG.

12. 1. Genetic Mutation of GDF15 & IGFBP7
• IGFBP7 – Insulin Growth Factor Binding Protein 7
• The gene that encodes IGF-7
• Gene involved in decidualization of gravid uterus.
• High levels are detected after implantation.
• IGFBP7 are highly expressed in the placenta.
• It plays a role in neuronal coordination of metabolism and feeding behavior,
nausea and vomition. It plays a role in the development of cachexia (s+s same
with HG).
• GDF15 and IGFBP7 levels are upregulated during placentation and cachexia,
and downregulated prior to miscarriage.
*When this gene is overexpressed, just like GDF15, it causes neuronal
dysregulation and overstimulation of vomition centers.

13. Gene Mutation of GDF15 and IGFBP7
Overexpression
GDF15-GFRAL
Transduction
Pathway is
overstimulated.
Cachexia
Excessive Nausea
and Vomiting,
Weight Loss.
HG-like
Symptoms
Brainstem Vomition
Center over-
activation.
Hyperemesis
Excessive Nausea
and Vomiting,
Weight Loss.

14. To be continued…..

15. High Estrogen Levels and HG
 It is known that estrogen levels causes relaxation of sphincters.
 Estrogen Participates in the regulation of GI motility and is involved in the
pathogenesis of various functional disorders in the stomach.
Important Terms:
 ER – estrogen receptors
 CGMP – cyclic guanine monophosphate
 GSMC – gastric smooth muscle cells
 NO-CGMP Pathway – responsible for relaxation of smooth muscles. That
are overexpressed in early pregnancy, than late pregnancy.
Estrogen has many biological effects in pregnancy:
1. Interrupted smooth muscle myoelectric and motor behavior
2. Lowered Gallbladder Contractile ability (polyuria)
3. Lower esophageal sphincter pressure
4. Delayed gastric emptying
5. Reduced Intestinal and Colonic Transit (slow peristalsis).

16. HOW?
-Estrogen stimulates the production of nitric
oxidase synthase (enzyme).
*Nitric Oxidase Synthase – the enzyme that
activates Nitric Oxide (NO).
*Nitric Oxide – stimulates the relaxation of
smooth muscles including the gallbladder,
trachea, urinary bladder, blood vessels, and
GI tract.

17.  Estrogen and progesterone targets other smooth muscle – made body organs
like GI Tract, Bladder, and Blood vessels.
 Estrogen Receptors are found in smooth muscles of GI, vasculature, and female
reproductive tract.
Note: Estrogen Plays an important role in HG because of Nitric Oxide

18. Increased Estrogen Levels
Increased Nitric Oxidase
Synthase Production
Increased Nitric Oxide
ACTIVATION
Relaxation of Smooth Muscles
Decreased
GI motility
Increased
rates of
Sphincter
Relaxation
Low Peristaltic
Movements
Increased GI
Distention
Stimulus from
Visceral
Afferents
from GI tract
to Trigger
CTZ (area
postrema of
brainstem)
Hyperemesis
Gravidarum
Note: GI Distention
is a potent stimulus
to trigger the
vomition centers to
induce vomiting.
*Low Peristaltic
movements also
contributes to a
Delayed Gastric
Emptying.

19. HCG and HG
 HCG – Human Chorionic Gonadotropin
Not YET
FINISHED