Anatomy of Respiratory System

Anatomy of Respiratory System

Organization and Functions of the Respiratory System
* Consists of an upper respiratory tract (nose to larynx) and a lower respiratory tract ( trachea onwards) .
* Conducting portion transports air.
- includes the nose, nasal cavity, pharynx, larynx, trachea, and progressively smaller airways, from the primary bronchi to the terminal bronchioles

* Respiratory portion carries out gas exchange.
- composed of small airways called respiratory bronchioles and alveolar ducts as well as air sacs called alveoli

Respiratory System Functions
* supplies the body with oxygen and disposes of carbon dioxide
* filters inspired air
* produces sound
* contains receptors for smell
* rids the body of some excess water and heat
* helps regulate blood pH

Breathing
* Breathing (pulmonary ventilation). consists of two cyclic phases:
* inhalation, also called inspiration - draws gases into the lungs.
* exhalation, also called expiration - forces gases out of the lungs.

Upper Respiratory Tract
* Composed of the nose and nasal cavity, paranasal sinuses, pharynx (throat), larynx.
* All part of the conducting portion of the respiratory system.
Respiratory mucosa
* A layer of pseudostratified ciliated columnar epithelial cells that secrete mucus
* Found in nose, sinuses, pharynx, larynx and trachea
* Mucus can trap contaminants
o Cilia move mucus up towards mouth

Upper Respiratory Tract

Nose
* Internal nares - opening to exterior
* External nares opening to pharynx
* Nasal conchae - folds in the mucous membrane that increase air turbulence and ensures that most air contacts the mucous membranes

Nose
* rich supply of capillaries warm the inspired air
* olfactory mucosa – mucous membranes that contain smell receptors
* respiratory mucosa – pseudostratified ciliated columnar epithelium containing goblet cells that secrete mucus which traps inhaled particles,
* lysozyme kills bacteria and lymphocytes and
* IgA antibodies that protect against bacteria

provides and airway for respiration
• moistens and warms entering air
• filters and cleans inspired air
• resonating chamber for speech
detects odors in the air stream
rhinoplasty: surgery to change shape of external nose

Paranasal Sinuses
* Four bones of the skull contain paired air spaces called the paranasal sinuses - frontal, ethmoidal, sphenoidal, maxillary
* Decrease skull bone weight
* Warm, moisten and filter incoming air
* Add resonance to voice.
* Communicate with the nasal cavity by ducts.
* Lined by pseudostratified ciliated columnar epithelium.

Paranasal sinuses

Pharynx
* Common space used by both the respiratory and digestive systems.
* Commonly called the throat.
* Originates posterior to the nasal and oral cavities and extends inferiorly near the level of the bifurcation of the larynx and esophagus.
* Common pathway for both air and food.
* Walls are lined by a mucosa and contain skeletal muscles that are primarily used for swallowing.
* Flexible lateral walls are distensible in order to force swallowed food into the esophagus.
* Partitioned into three adjoining regions:

nasopharynx
oropharynx
laryngopharynx
Nasopharynx
* Superior-most region of the pharynx. Covered with pseudostratified ciliated columnar epithelium.
* Located directly posterior to the nasal cavity and superior to the soft palate, which separates the oral cavity.
* Normally, only air passes through.
* Material from the oral cavity and oropharynx is typically blocked from entering the nasopharynx by the uvula of soft palate, which elevates when we swallow.
* In the lateral walls of the nasopharynx, paired auditory/eustachian tubes connect the nasopharynx to the middle ear.
* Posterior nasopharynx wall also houses a single pharyngeal tonsil (commonly called the adenoids).


Oropharynx
* The middle pharyngeal region.
* Immediately posterior to the oral cavity.
* Bounded by the edge of the soft palate superiorly and the hyoid bone inferiorly.
* Common respiratory and digestive pathway through which both air and swallowed food and drink pass.
* Contains nonkeratinized stratified squamous epithelim.
* Lymphatic organs here provide the first line of defense against ingested or inhaled foreign materials. Palatine tonsils are on the lateral wall between the arches, and the lingual tonsils are at the base of the tongue.

Laryngopharynx
* Inferior, narrowed region of the pharynx.
* Extends inferiorly from the hyoid bone to the larynx and esophagus.
* Terminates at the superior border of the esophagus and the epiglottis of the larynx.
* Lined with a nonkeratinized stratified squamous epithelium.
* Permits passage of both food and air.

Lower Respiratory Tract
* Conducting airways (trachea, bronchi, up to terminal bronchioles).
* Respiratory portion of the respiratory system (respiratory bronchioles, alveolar ducts, and alveoli).
Larynx
* Voice box is a short, somewhat cylindrical airway ends in the trachea.
* Prevents swallowed materials from entering the lower respiratory tract.
* Conducts air into the lower respiratory tract.
* Produces sounds.
* Supported by a framework of nine pieces of cartilage (three individual pieces and three cartilage pairs) that are held in place by ligaments and muscles.
* Nine c-rings of cartilage form the framework of the larynx
* thyroid cartilage – (1) Adam’s apple, hyaline, anterior attachment of vocal folds, testosterone increases size after puberty
* cricoid cartilage – (1) ring-shaped, hyaline
* arytenoid cartilages – (2) hyaline, posterior attachment of vocal folds, hyaline
* cuneiform cartilages - (2) hyaline
* corniculate cartlages - (2) hyaline

epiglottis – (1) elastic cartilage
* Muscular walls aid in voice production and the swallowing reflex
* Glottis – the superior opening of the larynx
* Epiglottis – prevents food and drink from entering airway when swallowing
* pseudostratified ciliated columnar epithelium

Sound Production
* Inferior ligaments are called the vocal folds.
- are true vocal cords because they produce sound when air passes between them
* Superior ligaments are called the vestibular folds.
- are false vocal cords because they have no function in sound production, but protect the vocal folds.

* The tension, length, and position of the vocal folds determine the quality of the sound.

Sound production
* Intermittent release of exhaled air through the vocal folds
* Loudness – depends on the force with which air is exhaled through the cords
* Pharynx, oral cavity, nasal cavity, paranasal sinuses act as resonating chambers that add quality to the sound
* Muscles of the face, tongue, and lips help with enunciation of words

Conducting zone of lower respiratory tract
Trachea
* A flexible tube also called windpipe.
* Extends through the mediastinum and lies anterior to the esophagus and inferior to the larynx.
* Anterior and lateral walls of the trachea supported by 15 to 20 C-shaped tracheal cartilages.
* Cartilage rings reinforce and provide rigidity to the tracheal wall to ensure that the trachea remains open at all times
* Posterior part of tube lined by trachealis muscle
* Lined by ciliated pseudostratified columnar epithelium.
Trachea
* At the level of the sternal angle, the trachea bifurcates into two smaller tubes, called the right and left primary bronchi.
* Each primary bronchus projects laterally toward each lung.
* The most inferior tracheal cartilage separates the primary bronchi at their origin and forms an internal ridge called the carina.
Bronchial tree
* A highly branched system of air-conducting passages that originate from the left and right primary bronchi.
* Progressively branch into narrower tubes as they diverge throughout the lungs before terminating in terminal bronchioles.
* Incomplete rings of hyaline cartilage support the walls of the primary bronchi to ensure that they remain open.
* Right primary bronchus is shorter, wider, and more vertically oriented than the left primary bronchus.
* Foreign particles are more likely to lodge in the right primary bronchus.
* The primary bronchi enter the hilus of each lung together with the pulmonary vessels, lymphatic vessels, and nerves.
* Each primary bronchus branches into several secondary bronchi (or lobar bronchi).
* The left lung has two secondary bronchi.The right lung has three secondary bronchi.
* They further divide into tertiary bronchi.
* Each tertiary bronchus is called a segmental bronchus because it supplies a part of the lung called a bronchopulmonary segment.
* Secondary bronchi tertiary bronchi bronchioles terminal bronchioles
* with successive branching amount of cartilage decreases and amount of smooth muscle increases, this allows for variation in airway diameter
* during exertion and when sympathetic division active bronchodilation
* mediators of allergic reactions like histamine bronchoconstriction
* epithelium gradually changes from ciliated pseudostratified columnar epithelium to simple cuboidal epithelium in terminal bronchioles

Respiratory Zone of Lower Respiratory Tract
Conduction vs. Respiratory zones
* Most of the tubing in the lungs makes up conduction zone
o Consists of nasal cavity to terminal bronchioles
* The respiratory zone is where gas is exchanged
o Consists of alveoli, alveolar sacs, alveolar ducts and respiratory bronchioles

Respiratory Bronchioles, Alveolar Ducts, and Alveoli
* Lungs contain small saccular outpocketings called alveoli.
* They have a thin wall specialized to promote diffusion of gases between the alveolus and the blood in the pulmonary capillaries.
* Gas exchange can take place in the respiratory bronchioles and alveolar ducts as well as in the alveoli, each lung contains approximately 300 to 400 million alveoli.
* The spongy nature of the lung is due to the packing of millions of alveoli together.

Respiratory Membrane
* squamous cells of alveoli .
* basement membrane of alveoli.
* basement membrane of capillaries
* simple squamous cells of capillaries
* about .5 μ in thickness

Gross Anatomy of the Lungs
* Each lung has a conical shape. Its wide, concave base rests upon the muscular diaphragm.
* Its superior region called the apex projects superiorly to a point that is slightly superior and posterior to the clavicle.
* Both lungs are bordered by the thoracic wall anteriorly, laterally, and posteriorly, and supported by the rib cage.
* Toward the midline, the lungs are separated from each other by the mediastinum.
* The relatively broad, rounded surface in contact with the thoracic wall is called the costal surface of the lung.

Left lung
* divided into 2 lobes by oblique fissure
* smaller than the right lung
* cardiac notch accommodates the heart
Right
* divided into 3 lobes by oblique and horizontal fissure
* located more superiorly in the body due to liver on right side

Pleura and Pleural Cavities
* The outer surface of each lung and the adjacent internal thoracic wall are lined by a serous membrane called pleura.
* The outer surface of each lung is tightly covered by the visceral pleura.
* while the internal thoracic walls, the lateral surfaces of the mediastinum, and the superior surface of the diaphragm are lined by the parietal pleura.
* The parietal and visceral pleural layers are continuous at the hilus of each lung.

Pleural Cavities
The potential space between the serous membrane layers is a pleural cavity.

* The pleural membranes produce a thin, serous pleural fluid that circulates in the pleural cavity and acts as a lubricant, ensuring minimal friction during breathing.
* Pleural effusion – pleuritis with too much fluid
Blood supply of Lungs
* pulmonary circulation -
* bronchial circulation – bronchial arteries supply oxygenated blood to lungs, bronchial veins carry away deoxygenated blood from lung tissue  superior vena cava
* Response of two systems to hypoxia – pulmonary vessels undergo vasoconstriction bronchial vessels like all other systemic vessels undergo vasodilation

Respiratory events
* Pulmonary ventilation = exchange of gases between lungs and atmosphere
* External respiration = exchange of gases between alveoli and pulmonary capillaries
* Internal respiration = exchange of gases between systemic capillaries and tissue cells

Two phases of pulmonary ventilation
* Inspiration, or inhalation - a very active process that requires input of energy.The diaphragm, contracts, moving downward and flattening, when stimulated by phrenic nerves.
* Expiration, or exhalation - a passive process that takes advantage of the recoil properties of elastic fiber. ･The diaphragm relaxes.The elasticity of the lungs and the thoracic cage allows them to return to their normal size and shape.

Muscles that ASSIST with respiration
* The scalenes help increase thoracic cavity dimensions by elevating the first and second ribs during forced inhalation.
* The ribs elevate upon contraction of the external intercostals, thereby increasing the transverse dimensions of the thoracic cavity during inhalation.
* Contraction of the internal intercostals depresses the ribs, but this only occurs during forced exhalation.
* Normal exhalation requires no active muscular effort.

Muscles that ASSIST with respiration
* Other accessory muscles assist with respiratory activities.
* The pectoralis minor, serratus anterior, and sternocleidomastoid help with forced inhalation,
* while the abdominal muscles(external and internal obliques, transversus abdominis, and rectus abdominis) assist in active exhalation.

Boyle’s Law
* The pressure of a gas decreases if the volume of the container increases, and vice versa.
* When the volume of the thoracic cavity increases even slightly during inhalation, the intrapulmonary pressure decreases slightly, and air flows into the lungs through the conducting airways. Air flows into the lungs from a region of higher pressure (the atmosphere)into a region of lower pressure (the intrapulmonary region).
* When the volume of the thoracic cavity decreases during exhalation, the intrapulmonary pressure increases and forces air out of the lungs into the atmosphere.

Ventilation Control by Respiratory Centers of the Brain
* The trachea, bronchial tree, and lungs are innervated by the autonomic nervous system.
* The autonomic nerve fibers that innervate the heart also send branches to the respiratory structures.
* The involuntary, rhythmic activities that deliver and remove respiratory gases are regulated in the brainstem within the reticular formation through both the medulla oblongata and pons.

Respiratory Values
* A normal adult averages 12 breathes per minute = respiratory rate(RR)
* Respiratory volumes – determined by using a spirometer

LUNG VOLUMES
* TIDAL VOLUME (TV): Volume inspired or expired with each normalﾊbreath. = 500 ml
* INSPIRATORY RESERVE VOLUME (IRV): Maximum volume that can be inspired over the inspiration of a tidal volume/normal breath. Used during exercise/exertion.=3100 ml
* EXPIRATRY RESERVE VOLUME (ERV): Maximal volume that can be expired after the expiration of a tidal volume/normal breath. = 1200 ml
* RESIDUAL VOLUME (RV): Volume that remains in the lungs after a maximal expiration.ﾊ CANNOT be measured by spirometry.= 1200 ml

LUNG CAPACITIES
* INSPIRATORY CAPACITY ( IC): Volume of maximal inspiration:IRV + TV = 3600 ml
* FUNCTIONAL RESIDUAL CAPACITY (FRC): Volume of gas remaining in lung after normal expiration, cannot be measured by spirometry because it includes residual volume:ERV + RV = 2400 ml
* VITAL CAPACITY (VC): Volume of maximal inspiration and expiration:IRV + TV + ERV = IC + ERV = 4800 ml
* TOTAL LUNG CAPACITY (TLC): The volume of the lung after maximal inspiration.ﾊ The sum of all four lung volumes, cannot be measured by spirometry because it includes residual volume:IRV+ TV + ERV + RV = IC + FRC = 6000 ml

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Upper Respiratory Tract Infections

Upper Respiratory Tract Infections
By:Dr. Meenakshi Aggarwal MD
Emory Family Medicine

Definition

* Inflammation of the respiratory mucosa from the nose to the lower respiratory tree, not including the alveoli.

Objectives
* List the various categories of upper respiratory tract infections
* Obtain a pertinent history in a patient with a suspected URI.
* Perform a targeted and thorough physical examination to confirm the diagnosis of URI.
* Perform and interpret selected tests to diagnose URI
* Manage and treat uncomplicated URI’s.

Categories
* Acute Rhinosinusitis
* Acute Pharyngitis
* Acute Bronchitis

Differential Diagnosis
* Influenza
* Pneumonia
* Tuberculosis
* Asthma

Anatomy of Sinuses
Acute Rhinosinusitis (Viral)
* Common Symptoms: Nasal discharge, nasal congestion, facial pressure, cough, fever, muscle aches, joint pains, sore throat with hoarseness.
* Symptoms resolve in 10-14 days
* Common in fall, winter and spring.
* Treatment: Symptomatic

Acute Bacterial Sinusitis
* Causative agents are usually the normal inhabitants of the respiratory tract.
* Common agents:

Streptococcus pneumoniae
Nontypeable Haemophilus Influenzae

Moraxella Catarrhalis
Signs and Symptoms
* Feeling of fullness and pressure over the involved sinuses, nasal congestion and purulent nasal discharge.
* Other associated symptoms: Sore throat, malaise, low grade fever, headache, toothache, cough > 1 week duration.
* Symptoms may last for more than 10-14 days.

Diagnosis
* Based on clinical signs and symptoms
* Physical Exam: Palpate over the sinuses, look for structural abnormalities like DNS.
* X-ray sinuses: not usually needed but may show cloudiness and air fluid levels
* Limited coronal CT are more sensitive to inflammatory changes and bone destruction

Ethmoid Sinusitis
Coronal computed tomographic scan showing ethmoidal polyps. Ethmoid opacity is total as a result of nasal polyps, with a secondary fluid level in the left maxillary antrum.

Treatment
* About 2/3rd of patients will improve without treatment in 2 weeks.
* Antibiotics: Reserved for patients who have symptoms for more than 10 days or who experience worsening symptoms.
* OTC decongestant nasal sprays should be discouraged for use more than 5 days
* Supportive therapy: Humidification, analgesics, antihistaminics
a) Amoxicillin (500mg TID) OR
b) TMP/SMX ( one DS for 10 days).
c) Alternative antibiotics: High dose amoxi/clavunate, Flouroquinolones, macrolides

Antibiotics
Acute Pharyngitis
* Fewer than 25% of patients with sore throat have true pharyngitis.
* Primarily seen in 5-18 years old. Common in adult women.

Etiology
A) Viral: Most common.
Rhinovirus (most common).
Symptoms usually last for 3-5 days.

B) Bacterial: Group A beta hemolytic streptococcus (GABHS).
Early detection can prevent complications like acute rheumatic fever and post streptococcal GN.

Signs and Symptoms
* Absence of Cough
* Fever
* Sore throat
* Malaise
* Rhinorrhoea
* Classic triad of GABHS: High fever, tonsillar exhudates and ant. cervical lymphadenopathy.

NO COUGH
Diagnosis
* Physical Exam: Tonsillar exhudates, anterior cervical LAD
* Rapid strep: Throat swab. Sensitivity of 80% and specificity of 95%.

Throat Cultures: Not required usually. Needed only when suspicion is high and rapid strep is negative.

Exhudates
Management
A) Symptomatic: Saline gargles,

analgesics, cool-mist humidification and throat lozenges.

B) Antibiotics:
a) Benzathine Pn-G 1.2 million units IM x 1OR Pn V orally for 10 days
b) For Pn allergic pts:Erythromycin 500mg QID x 10 days OR Azithro 500 mg Qdaily x 3 days.

Acute Bronchitis
Inflammation of the bronchial respiratory mucosa leading to productive cough.
Acute Bronchitis
* Etiology: A)Viral
B) Bacterial (Bordetella pertussis, Mycoplasma pneumoniae, and Chlamydia pneumoniae)
* Diagnosis: Clinical
* S/S: Productive cough, rarely fever or tachypnea.

Treatment
* Symptomatic
* If cough persists for more than 10 days:

Azithro x 5 days OR
Clarithro x 7 days
Non specific URI’s

* Common Cold
* Etiology: Rhinovirus
Adenovirus
RSV
Parainfluenza
Enteroviruses
Diagnosis: Clinical
Treatment: Adequate fluid intake, rest, humidified air, and over-the-counter analgesics and antipyretics.

Influenza
* Etiology: Influenza A & B
* Symptoms: Fever, myalgias, headache, rhinitis, malaise, nonproductive cough, sore throat
* Diagnosis: Influenza A &B antigen testing
* Treatment: Supportive care, oseltamivir, amantidine

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Hepatitis A & B

Hepatitis A

The virus that does not cause chronic liver disease

Hepatitis A
* “Infectious Hepatitis”
* First characterized in 1973
* Detected in human feces
* Hepatovirus genus
* A reportable infectious disease
* U.S. rate of infection 4/100,000
* Highest among children

Risk Factors
* Sexual or household contact
* International travel
* Men who have sex w/ men (MSM)
* Intravenous drug abuse (IVDA)
* Daycare

Transmission
* Unwitting contact w/ infected person
* Most cases unknown
* Primary route is fecal oral either by person to person contact or ingestion of contaminated food or water

Pathogenesis
* After ingestion, the HAV survives gastric acid, moves to the small intestine and reaches the liver via the portal vein
* Replicates in hepatocyte cytoplasm
o Not a cytopathic virus
o Immune mediated cell damage more likely
* Once mature the HAV travels through sinusoids and enters bile canaliculi, released into the small intestine and systemic circulation, excreted in feces

Clinical Features
* Incubation is usually 2 to 4 weeks, rarely 6 weeks
* Complete recovery within 2 months for > 50%
* Within 6 months for almost all others
* Low mortality in healthy people
o High mortality when older than age 60
o High in presence of chronic liver disease
* High morbidity
o Around 20% need hospitalization
o Lost work days
o Most become jaundiced
* Asymptomatic < 2 year old * Symptomatic – 5 and older ill about 8 weeks * Cholestatic – jaundice lasts > 10 weeks
* Relapsing w/ 2 or more bouts acute HAV over a 6 to 10 week period
* Acute liver failure – rare in young. When it occurs, is rapid i.e., within 4 weeks

Signs and Symptoms
* Prodrome lasts 1-2 weeks: fatigue, asthenia, anorexia, nausea, vomiting, and abdominal pain
* Less common: fever, cephalgia, arthralgia, myalgia, and diarrhea
* Dark urine is followed by jaundice and hepatomegaly
* Less common: splenomegaly, cervical lymphadenopathy

Diagnosis
* During acute infection, anti HAV IgM appears first
* HAV IgG antibody appears early in the course of infection and remains detectable for life, providing lifelong immunity

Prevention Immunization
* All children 12 – 24 months
* Travelers, occupational exposure risk
* All patients w/ hepatitis B or C or those awaiting liver transplantation
* HIV positive patients
* MSM
* IVD users
* People w/ clotting factor deficiencies
* Lab workers handling live hepatitis A vaccine
* Need for post exposure prophylaxis uncommon. Administration of the vaccine is effective. If needed, administer immune serum globulin within 2 weeks 0.02 ml/Kg IM

Hepatitis A Vaccine
* The vaccine is inactivated HAV
* Schedule for 2 – 18 years depends upon the manufacturer:
o Havirx: 720 EL U/.5mL @ 0, 6-12 mo
o Vaqta: 25 U.5mL @ 0, 6-18 mo
* For those over age 18:
o Havirx: 1440 EL U/1mL @ 0, 6-12 mo
o Vaqta: 50 U/1mL @ 0, 6-18 mo
* Adverse effects: rarely anaphylaxis, injection site induration, erythema, edema, fatigue, mild fever, malaise, anorexia, nausea
* Twinrix:
o 720 El U/1mL 0, 1, 6 mo plus
o 20 mcg HBV

Questions?
Hepatitis B
The Virus
* The hepatitis B virus is among the smallest genomes of all known animal viruses
* A DNA virus that infects only humans
* Belongs to the family Hepadnaviridae
* Knowledge of the viral proteins that are perceived by the immune system as “antigens” aids understanding of the various tests used to diagnose acute, chronic, and resolved infection and verify response to immunization

HBV Antigens
* Outer envelope contains a surface protein called hepatitis B surface antigen
* HBsAg is a marker of viral replication
* Inner core contains the genome, the DNA polymerase w/ reverse transcriptase activity, hepatitis B core antigen (HBcAg) particles. This antigen is not detectable in serum
* A truncated form of the major core polypeptide known as hepatitis e antigen (HBeAg) is the third antigen generated by virus activity. Marker of high infectivity

Hepatitis B Antibodies
* Hepatitis B surface antibody is the antibody to surface antigen. HBsAb is protective and indicates either resolved infection or immunization
* HBcAb is the antibody to core antigen. This is not a protective antibody. Only those who have been exposed to the virus will have this antibody
* HBcAb is measured in serum as:
o Anti HBc IgM (usually indicates new infection)
o Anti HBc IgG (appears later)
* HBeAb is the antibody to e antigen. Loss of e antigen w/ gain of e antibody is called seroconversion. Not a protective antibody

Epidemiology
* Prevalence of HBV varies markedly around the world, w/ > 75% of cases in Asia and the Western Pacific
* Vaccine available > 20 years, but perinatal and early life exposure continue to be a major source of infection in endemic areas
* Most acute HBV cases in the U.S. are seen among young adults, males > females, who use injection drugs and in those who engage in high risk sexual behaviors
* In the U.S., hundreds of people die each year of fulminant HBV
* World wide, chronic HBV and its complications including hepatocellular carcinoma account for > 1 million deaths each year

Risk Factors

* Percutaneous and mucous membrane exposure. The virus is 100 x more infectious than HIV, 10 x more infectious than HCV and is present in all body fluids. Present on horizontal surfaces, eating utensils, personal hygiene items, etc.
* Babies born to infected mother
* Household contact
* Hemodialysis
* Receipt of blood products prior to the early 1970s
* Receipt of previously infected donor liver

Markers of Exposure
* Surface antigen appears as early as 1-2 weeks following exposure, as late as 11-12 weeks
* HBV DNA measurable soon after
* HBeAg appears shortly after HBsAg
* Hepatitis occurs 1 – 7 weeks after appearance of HBsAg

Pathophysiology
* Governed by interaction between the virus and host immune response
* Following inoculation by the HBV, cytokine release, cell injury and viral clearance follow
* HBsAg disappears by six months and is accompanied by sero conversion to protective HBsAb
* Persistent virus replication after six months ->chronic hepatitis and is the result of a compromised (newborn/HIV) or relatively tolerant immune system status

Four Stages of Infection
* Age at time of infection predicts chronicity in most cases. Infants and young children usually become chronically infected. When acquired in adults, the virus is cleared by the healthy immune system in about 95% of cases, leading to natural immunity
* Immune tolerant phase, there is active viral replication. ALT and AST are normal. Immune system does not recognize HBV as “foreign”
* In the immune clearance phase, enzymes rise reflecting immune mediated lysis of infected hepatocytes. This phase can last for years. Seroconversion of HBeAg to HBeAb occurs

Stages of Infection
* Low or non-replicative phase. Also known as inactive carrier (or inappropriately “healthy carrier”). Characterized by resolution of necroinflammation, normalization of enzymes and low levels of HBV DNA. This stage may last for life
* Reactivation. Spontaneous or immunosuppression mediated (cancer chemotherapy or high dose corticosteroid therapy)

Signs and Symptoms
* Incubation period: a few weeks to 6 months
* About 30% develop jaundice
* 10% to 20% of patients develop serum sickness, i.e., fever, arthralgias, rash
* Fulminant hepatitis B occurs in < 1% of cases. 80% mortality without liver transplantation * Enzyme elevations of 1,000-2,000 typical Signs and Symptoms * Fatigue, RUQ discomfort may be the only symptoms * Those in the immune tolerant phase are usually asymptomatic. The phase lasts until late puberty into adulthood Signs of Decompensation * See section on Cirrhosis and Portal Hypertension * Refer to a liver transplantation center * Patient education for people with chronic liver disease should be reinforced * Refer to “Ten Tips for People w/ Chronic Liver Disease” Prevention * Two forms of vaccine now available. * Twinrix – contains both hepatitis A and B vaccines available in an accelerated schedule or standard series * Individual hepatitis B vaccine * Standard schedule is given: o Time 0 o 1 mo o 6 mo Prevention * Educate to avoid IVDU, high risk sexual activity * Prevent peri natal transmission. Serology of pregnant women for HBsAg is standard of practice in U.S. * If pregnant female has high viremia, refer to hepatologist for treatment during the 3rd trimester to reduce risk of transmission to neonate * Babies of HBsAg mothers receive hepatitis B immune globulin with 12 hours of birth and begin the vaccine series immediately Treatment * Six approved medications as of July 2008 o Interferon alpha o Pegylated interferon o Lamivudine o Adefovir Dipivoxil o Entecavir o Telbivudine o Tenofovir approved * Refer to hepatologist The Cholestatic Liver Diseases Adults Cholestatic Liver Disease Etiologies * Immune Mediated: PBC, PSC, autoimmune cholangitis, liver allograft rejection, graft-versus-host disease * Infectious: acute viral hepatitis * Genetic and Developmental: cystic fibrosis, Alagille’s syndrome (syndrome w/ paucity of intrahepatic bile ducts), fibro polycystic liver disease * Neoplastic: Cholangiocarcinoma * Drug-Induced Ductopenia: amoxicillin, amitriptyline, cyproheptadine, erythromycin, tetracycline, thiabendazole * Ischemic * Idiopathic Pathogenesis of Cholestatic Disorders * Immune response (inflammation, auto-antibody) or hepatotoxic injury to bile ducts * Bile duct injury by bile acids - >
* Retention of bile acids in hepatocytes - >
* Liver cell damage, apoptosis, necrosis, fibrosis, cirrhosis - > liver failure

Complications of Chronic Cholestasis
* Pruritis believed to be 2/2 increased opioid receptor tone, or centrally mediated
* Fatigue
* Bone disease: osteopenia, osteoporosis
* Fat soluble vitamin deficiency
* Malabsorption (Sprue, bile salt deficiency, pancreatic insufficiency)

Pruritis in Cholestasis

* Therapy:
o Urso in AICP, PBC (15-30mg/Kg/day)
o Opiate antagonist naltrexone (50mg/day)
o 5-HT3 antagonist odansetron
o SSRI sertaline
o Bile acid sequesterant cholestyramine 4gm t.i.d. to q.i.d.
o Antihistamines rarely effective
o Rifampin 150mg to 300mg b.i.d.

Fatigue in Cholestasis
* High prevalence in Primary Biliary Cirrhosis unrelated to disease severity or duration
* Pathogenesis
o ?decreased hypothalamic cortico-tropin-releasing hormone
o ?CNS accumulation of manganese
* Prognosis worse
* No effective treatment

Bone Disease in Cholestasis
* Clinical manifestations: low bone density, fractures of axial and/or appendicular skeleton
* Pathogenesis: hyperbilirubinemia impairs osteoblast proliferative activity
* Therapy: bisphosphonates, calcium, vitamin D, weight bearing exercise, estrogens appear to be safe

1. Primary Biliary Cirrhosis
A chronic and progressive disease of unknown etiology affecting primarily middle-aged women

Primary Biliary Cirrhosis
* Affects all races
* 9:1 ratio female > male, age 20 – 65
* Characterized by small intrahepatic bile duct destruction and cholestasis
* In the presence of cirrhosis, male > likely than female to develop hepatocellular carcinoma

PBC
Laboratory Findings
* Alk Phos 2x to 20x ULN in > 90% of patients
* AST-ALT 1x to 5x ULN > 90%
* Bilirubin – variable. When elevated, may indicate advanced cirrhosis or 2nd condition
* Hypercholesterolemia in 80% of patients

Hypercholesterolemia Unique in PBC
* Hypercholesterolemia
* IgM 1x to 5x ULN > 90%
* Anti mitochondrial antibody > 1:20 titer >90%
* Anti nuclear and/or smooth muscle antibody > 1:80 may be seen in “overlap syndrome”
* Liver biopsy helpful to grade and stage disease, determine if cirrhosis present

PBC Treatment
* Slowly progressive, even if asymptomatic
* Ursodeoxycholic acid only effective therapy. May improve natural history
* Transplant curative
* Manage disease specific complications

Effects of Ursodeoxycholate
* Urso is a hydrophilic bile acid having multiple anti-inflammatory and immunomodulatory actions
* Urso administration in the setting of pro-apoptotic stimuli (bile salts, ethanol, TGF-beta, FAS ligand) inhibits in vitro apoptosis (programmed cell death)
* Reduces mitochondrial membrane permeability

Monitor for and Treat PBC Associated Disorders
* Keratoconjunctivitis Sicca
* Scleroderma, CREST syndrome
* Gallstones
* Arthropathies:
o Rheumatoid, psoriatic arthritis, Raynaud’s phenomenon, Hypertrophic osteodystrophy, Avascular necrosis, Chondrocalcinosis
* Thyroid disease, renal tubular acidosis

PBC Associated Disorders
* Malabsorption
* Celiac Sprue
o 6% of PBC patients have Celiac Sprue
o 3% of Sprue patients have PBC
* Bile salt deficiency
* Pancreatic insufficiency

Manage PBC Complications
* Standard liver disease recommendations
* PBC specific symptom management
* Refer for liver transplantation
* Primary Sclerosing Cholangitis
Rare
* One of the most important cholestatic liver diseases in the western world
* Chronic, cholestatic liver disease characterized by
o Inflammation
o Obstruction
o Fibrosis of both intrahepatic and extrahepatic bile ducts

Primary Sclerosing Cholangitis
* Many patients will progress to cirrhosis
* Highly variable in and between individuals
* Usually fatal important complication is cholangiocarcinoma
* Etiology largely unknown, though evidence points to immune system involvement

PSC
* No specific treatment
* Treatment aimed at management of disease associated conditions
* Prevalence unknown
* Almost half are asymptomatic at diagnosis
* No specific diagnostic marker for PSC

PSC Clinical Features
* Labs:
o Two- fold increase in alk phos, most have increased AST and ALT
o Albumin and protime normal in early disease
o Bilirubin initially normal, but gradually increases and fluctuates widely w/ extrahepatic biliary strictures, infection, obstructing stone sludge or stone
* Imaging
* Magnetic resonance cholangio-pancreatography demonstrates intrahepatic duct changes
* Histology
* Liver biopsy for staging the disease
* Liver biopsy to rule out other potentially treatable causes of cholestasis

PSC Patient Presentation
* Large bile duct PSC may have asymptomatic elevation of LFTs. Can be cirrhotic w/ no symptoms
* Symptomatic patients will have cholestasis-type symptoms plus:
o Abdominal pain
o Weight loss
o Hepatomegaly
o Acute cholangitis

PSC Associated Diseases
* Inflammatory bowel disease, most often ulcerative colitis
* These patients have increased risk for colorectal carcinoma
* 25% have another autoimmune disease

PSC Complications
* Related to cholestasis: pruritis, fatigue, fat soluble vitamin deficiency, osteoporosis
* Related to cirrhosis: liver failure, peristomal varices
* Extra-hepatic disease: IBD, pancreatitis, sprue, diabetes, thyroid disease
* PSC specific

PSC Disease Specific Complications
* Fever
* Abdominal pain
* Dominant stricture
* Gall stones
* Cholangiocarcinoma

PSC Prognosis
* Factors of Importance:
o Older age
o Increasing bilirubin
o Histological advanced stage
o Child-Pugh-Turcotte Class C

PSC Treatment Goal Improve Quality of Life
* Medical support
* Endoscopic treatments
* Surgical interventions
* Liver transplantation – PSC recurrence is more frequent than PSC

Case Study
Reference

Hepatitis A & B .ppt

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