Pulmonary Arterial Hypertension - Basic Science and Rational of Therapeutics.

                                                Pulmonary Hypertension

                                            PKGhatak, MD

There are two separate circulatory systems - the greater and lesser circulatory systems. The greater system consists of the left atrium, left ventricle, aorta and its extensive branches to supply nutrients and oxygen to every living cell. This system is also called the Systemic Circulatory System. The lesser circulatory system consists of the right atrium, right ventricle and pulmonary artery and its branches to the lung alveoli. This is called the Pulmonary Circulatory system and this system delivers carbon dioxide to the lungs for elimination by ventilation and carries fully saturated oxygenated blood to the left atrium.

The circulating blood in the arterial tree exerts lateral pressure on the wall of the blood vessels and must overcome resistive wall pressure to propel forward. This wall resistance is called peripheral vascular resistance. This vascular resistance is commonly called Blood pressure - should be correctly called Systemic BP and Pulmonary BP.

Systemic blood pressure is easily measured on the arm by a BP instrument, either a mercury manometer or indirectly by a digital BP instrument which is properly calibrated. To measure the pulmonary arterial BP, a catheter must be inserted in the subclavian vein or femoral vein, then advanced to the right atrium, right ventricle, to the Pulmonary artery and then record the pulmonary arterial pressure. This invasive procedure is not practical for clinical practice.

In recent years, the Doppler Echocardiography and supplemented by 12 lead ECG, has to a greater extent, made monitoring pulmonary arterial BP much simpler and practical. The normal systemic BP is 120/80mm Hg and the normal pulmonary arterial BP is 20/10 mmHg.

These two circulatory systems are interconnected. The venous return of the systemic circulation comes to the right atrium via the superior vena cava and inferior vena cava. The venous blood from pulmonary circulation returns to the left atrium by pulmonary veins. This means diseases/ conditions of one, eventually, involve the other system.

Two other numbers are important in clinical practice - Mean Arterial Pressure (MAP) and Pulmonary Capillary Wedge Pressure (PCWR). MAP is the tissue perfusion pressure. The PCWR is a good approximation of the left atrial pressure.

MAP is calculated: MAP = (systolic BP /3) + (2x diastolic BP / 3).

The pulmonary artery/capillary wedge pressure is measured by a Swan Ganz catheter. This is obtained by advancing the catheter tip to the distant pulmonary arteriole and then inflating a small balloon to prevent pulmonary artery blood flow temporarily. The normal PCWR is 8 to 10 mm Hg.

In critically ill patients, pulmonary vascular resistance (PVR) is measured several times a day. PVR guides in adjusting fluids and vasopressor therapy, adjustment of ventilator settings, among other therapies. Pulmonary vascular resistance is calculated at the bedside from Swan Ganz catheter values.  Pulmonary artery pressure(PAP), pulmonary artery wedge pressure (PCWP) and cardiac output (CO) are necessary to calculate the PVR. 

 PVR =(PAP - PCWR) / CO.

In clinical medicine, PVR is expressed by using the Wood Unit.  Cardiac output is determined by thermodilution using cold saline. Woods unit is calculated using formula PVR = 80 x (PAP - PCWP) / CO. The normal PVR is 1 wood unit, a 3 Wood Unit is Pulmonary Arterial Hypertension or simply Pulmonary Hypertension.  In PAH the mean pulmonary BP is over 25 mm Hg, and PCWP is over 15mm Hg.

In physics, the Hagen-Poiseuille equation is used to determine the resistance of the tube using a formula R= 8 x L. n. r>4 (>4=raise to the power 4). Where R stands for resistance, L for the length of the tube, n for the viscosity of the fluid, and r for the radius of the tube.  In clinical medicine, the same equation remains valid. Variation of these parameters leads to pulmonary hypertension.

Pathological changes leading to hypertension:

Even a casual look at the Hagen-Poiseuille equation points out that a change in the lumen of the artery leads to a marked increase in BP. Regardless of different causes of PAH, there are common pathological changes in the pulmonary arterioles that produce narrowing of the arteriole lumen, increase PVR, hypertension and consequently right ventricular hypertrophy and cardiac failure and death. Pathological lesions are characterized by enhanced arteriolar smooth muscle contractility, dysfunctional arteriole due to aberrant remodeling of both endothelium and muscle layers and finally the microthrombi in capillaries.

Several of the following pathways are known to alter and result in pulmonary hypertension:

Nitrous oxide (NO) + soluble Guanylate cyclase pathway. The endothelial cells produce NO which binds with guanylate cyclase that produces guanosine triphosphate then transforms to guanosine monophosphate which is a potent vasodilator. It also prevents platelet aggregation and microthrombi.

Prostacyclin + Thromboxane A2 pathway. Prostacyclin is produced by the endothelial cells of arterioles. Prostacyclin binds with surface receptors of the smooth muscle cells, then activates ATP (adenosine triphosphate), and finally becomes cyclic AMP (adenosine monophosphate). AMP is anti-inflammatory and prevents platelet microthrombi.

Endothelin pathway.  Endothelin is a peptide, produced by the cell membrane of endothelial cells. It is a potent vasoconstrictor. Also produce smooth muscle hypertrophy, cell migration and fibrosis.

The reversible Hypoxic pathway.  The sympathetic nerve fibers abundantly supply even the smallest branches of pulmonary arterioles. The system is activated by chemoreceptors located in the carotid and aortic bodies. These receptors monitor PaO2 (partial pressure of oxygen); hypoxia causes reflex vasoconstriction and in prolonged hypoxemia migration of cells in and around arterioles produces fibrosis.

Clinical Classification of PAH:

PAH is categorized into 1. idiopathic, 2. familial, 3. secondary to other diseases, of which the most often are scleroderma and other collagen vascular diseases, HIV infection, portal hypertension, and congestive heart failure. 4. Drug induced and toxins.

Familial cases are due to the mutation of genes, the important gene mutations are: BMPR II, AIK I, ENG, SMAD 9, CAV 1, KCNK 3.

Drugs responsible for PAH are - Aminorex, Fenfluramine, Dexfenfluramine, Rapeseed oil, Benfluorex, several Serotonin reuptake inhibitors (SSRIs). Toxins - Tobacco smoke, chemical solvents.

Therapeutics:

There are no cures for pulmonary hypertension. Medications used for the treatment of systemic BP are ineffective in pulmonary hypertension. Treatment of pulmonary hypertension produces only slowing down the progression of the disease.

The following groups of drugs are used in pulmonary hypertension-

Phosphodiesterase inhibitors. - Sildenafil and Tadalafil.  Adenosine monophosphate and Guanosine monophosphates are converted to cyclic forms (c-AMP & c-GMP) by the action of adenylyl-cyclase and guanylyl-cyclase respectively. Cyclic AMP and cyclic GMP have a multitude of cellular functions including cell proliferation and growth. c-AMP and c-GMP are broken down by Phosphodiesterase. Sildenafil and Tadalafil inhibit the action of diesterase.

Soluble Guanylate cyclase stimulators. - Riociguat.  It increases intracellular cGMP.

Prostacyclin analogs. - Epoprostenol, Treprostinil, Iloprost. Prostacyclin produces smooth muscle relaxation, lowers pulmonary blood pressure, acts as an anti-inflammatory, inhibits platelet microthrombi.

Prostacyclin receptor agonist. - Selexipag. It is a vasodilator and prevents platelet adhesion.

Endothelial receptor antagonist. - Bosentan, Ambrisentan, Macitentan. Endothelin is a vasoconstrictor and increases pulmonary BP. These drugs prevent binding of Endothelin to its receptors and blunt the endothelin actions.

Additional agents used in the treatment of pulmonary hypertension are Oxygen, diuretics, nutrition and pulmonary rehabilitation.

Pulmonary hypertension detection by doppler echocardiogram is very useful for the diagnosis of new cases and monitoring the effects of therapy. More research is needed in pulmonary hypertension and in finding effective and less toxic drugs.

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Pleural Effusion - Cause and Mechanism:

 

                                                              Pleural Effusion

                                                      Mechanism and Causes

                                                    PKGhatak, MD

A small amount of pleural fluid is produced by the parietal pleura (a thin layer covering the inside of the chest wall, diaphragm and hilum), just enough to lubricate both layers of pleura so that during breathing the two surfaces slide smoothly one over the other without friction. The fluid does not accumulate because just as the fluid is produced continuously, the fluid is drained continuously by the lymphatic channels of the parietal pleura. Pleural effusion develops when excess fluid is produced or removal is delayed.

Clinical Types of Pleural Effusion:

It is useful to classify pleural effusion as Transudate and Exudate.

Transudate fluid is thin, has a low protein concentration, low LDH, and has none to two WBCs.

Transudate pleural effusion takes place because the fluid oozes out of the lung alveoli due to high capillary pressure. The most common cause of it is congestive heart failure, Nephrotic syndrome, cirrhosis of the liver, hypoalbuminemia from malabsorption syndrome, protein losing enteropathy and acute left ventricular failure, Pulmonary edema, and massive pulmonary embolism.

Mechanism of Transudate. Like liver nodules, the alveoli of the lung have a dual blood supply. The pulmonary artery brings in venous blood to the alveolar capillary. This is the source of most blood in the lung. In overloaded heart chambers in congestive heart failure, the pressure rises in heart chambers sharply. The back pressure is felt in the capillaries of the alveoli. When the pressure exceeds the oncotic pressure of blood, the water and dissolved solutes leak out in the interalveolar and pleural spaces resulting in pleural transudative pleural effusion.

Mechanism of Exudate: Inflammation of pleura by bacteria, mycobacteria tuberculosis, and fungus is generally due to the extension of lung infection. The pleural fluid is characterized by the presence of over 50% serum albumin concentration and over 60% LDH of the serum. The sugar concentration of the fluid in pneumococcal pleural effusion is low and has a high WBC count. 

Clinical subtypes of pleural effusion.

Empyema. In certain infections, the WBC numbers are so numerous that the pleural fluid becomes white cloudy- called empyema. Common causes of empyema are lung abscess rupturing in the pleural space, infected stab wounds, septicemia, post operative chest wounds. contaminated traumatic chest wall injuries.

Hemorrhagic Pleural Effusion. Traumatic chest wall injuries, contusion, laceration and infarction of the lung produce hemorrhage in the pleural space. Coagulation abnormalities either secondary to medical therapy, thrombocytopenia (platelet count 50,000 or less), deficiencies of coagulation factors or circulating anticoagulants may produce hemorrhagic pleural effusion.

Malignant Pleural Effusion. Malignant tumors of pleura are rather rare, only mesothelioma was an exception. In general, malignant pleural effusion is secondary to known lung malignancy, common in metastatic breast, ovary, colon cancers and primary lung cancer, lymphoma, and leukemias.

Chylous Pleural Effusion. The pleural fluid appears milky due to the presence of chylomicron. Chylomicrons contain long chain fatty acids, cholesterol esters, phospholipids. This condition results from obstruction or laceration of the thoracic duct. Cancer of the apical section of the lung. Pancoast tumors, lymphoma, and tuberculosis and filariasis cause obstruction of the thoracic duct. Fractures of 1st rib, sternum and upper thoracic vertebrae may cause laceration of the thoracic duct.

Bilateral Pleural Effusion. It is due to systemic diseases like CHF, nephrotic syndrome, cirrhosis, etc.

Unilateral Pleural Effusion. Unilateral effusion is due to one sided pleural disease but subsequently may be bilateral, if the disease spread to the other side. Example- pneumonia.

Localized Pleural effusion. The accumulated pleural fluid is walled off by fibrin and coagulated proteins.

Pleural Thickening. In tubercular pleural effusion, if the pleural fluid is not by evacuated by thoracentesis or drug therapy, layers of fibrous tissues are deposited over the surface of the lung like a straitjacket and prevent the expansion of the lung during breathing.

Cryptogenic or Unknown Causes of Pleural effusion. The effusion may start as unilateral or bilateral, and transudate effusion may turn exudate. In long term follow up and repeated pleural biopsies, detect about 10% due to mesothelioma or carcinoma of the lung. The cause of the remaining cases remains unknown.

Chronic Pleural Effusion. This condition is usually associated with end organ failure.

Rare causes of Pleural Effusion.

Meig's syndrome. Pleural effusion and ascites are associated with a benign ovarian tumor.

Ovarian Overstimulation Syndrome. Injectable fertility drugs to generate eggs in ovaries may produce capillary leaks and ascites and pleural effusion may develop.

Post Radiation Therapy also for the same reason produces this complication.

 Allergic drug reactions, Collagen vascular diseases and Autoimmune diseases can cause a mild form of vasculitis and pleural effusion.

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Multiple Myeloma

                                                          Multiple Myeloma

                                                   PKGhatak, MD

Multiple Myeloma (MM) is a cancerous disease of the Plasma cells of the bone marrow. It is a disease of the elderly and the condition is not inherited nor are there any known risk factors; but hepatitis C, HIV infection and Chronic Lymphocytic leukemia (CLL) patients have a higher incidence of MM.

MM is the final stage of a spectrum of plasma cell dyscrasias which starts as monoclonal gammopathy of unknown significance (MGUS) to overt plasma cell leukemia to extramedullary myeloma and finally to MM with end organ damages.

Epidemiology:

MM is very rare in people under 35 years. old. The annual incidence of MM in the USA is 300,000/yr. and 12,000 people die from MM. The worldwide incidence of MM is 80,000/yr.  New Zealand and Australia have more MM per 100,000 population. In the USA, the rate is 8.2 in white men, 5.0 in women, 16.5 in black men and 12.0 in black women per 100,000 population. For Hispanic men and women, the rates are 8.2 and 5.7 respectively and the rate for Asian/Pacific islanders at 5.0 in men and 3.2 in women.

Plasma Cell.

                                            Plasma cell..

About 2 to 3% of cells in the normal bone marrow are plasma cells. Plasma cells are large and have an eccentric nucleus, coarse chromatin and large cytoplasm.

In health, the majority of plasma cells are found in the active bone marrow and a few are also found in the spleen, lymph nodes and other tissues. In adults, the most active marrow is located in the vertebrae, scapula, sternum, skull bones, ribs and pelvis. The plasma cells are derived from B-lymphocytes (B-cells). B-cells are activated by a specific foreign antigen, which is introduced to them by the Dendritic cells. Activated B-cells in lymph nodes survive only 4-5 days. Some activated B-cells move to the bone marrow and live for a very long time. Bone marrow plasma cell keeps that antigen memory permanently. When challenged again with the same antigen, they quickly produce IgM antibodies (Immunoglobulin) and 10 days later start making IgG antibodies and keep producing antibodies as long as that antigen remains in the body or is reintroduced at a later time. IgA, IgD, IgE antibodies are also produced by plasma cells in various amounts and based on their location in the tissue/organ.

Effects of Uncontrolled growth of Plasma cells.

Rapidly multiplying plasma cells displace other blood forming cells, and soon the plasma cells number grows to 60 to 80 % of the bone marrow blood forming cells. RBC, WBC and Platelet numbers decrease and anemia, recurrent infection and easy bruising develop. The secretory product of plasma cells is immunoglobulins. In MM the immunoglobulins are abnormal in both structure and amounts. The accumulated immunoglobulin in blood makes blood more viscous and blood circulation in capillaries becomes sluggish, particularly in the retinal vessels, producing retinal hemorrhage and decreased visual acuity. The lambda and kappa light chains of immunoglobulins are excreted in urine, and gradually renal function deteriorates. Bone spicules dissolve and lytic lesions are detected in an x-ray. Blood calcium levels rise in proportion to bone lysis and osteoporosis and high serum calcium usually leads to a serious medical emergency.

Symptoms of MM:

In those days before Google search, medical schools came up with mnemonics to help students memorize certain important symptoms of a disease. CRAB stood for symptoms of MM. C=calcium increase in blood, R= renal function deterioration, A= anemia, B=bone pain. Bone pain is worse at dawn and dusk and increases in intensity with physical activities. Another mnemonic is Poem syndrome. P=peripheral neuropathy, O=organomegaly,  E= endocrinopathy. M=macroglobulin levels. S=skin pigmentation changes.

 Various peripheral nerves are involved, the Liver, and the spleen are enlarged, and many endocrine secretions are suboptimal. Thicken skin, changes in hair growth over the face, chest, limbs, and edema of legs and feet may develop. Other symptoms are weight loss, weakness, fatigue, confusion, and dementia.

Clinical subtypes of MM:

1. Indolent MM - patients are asymptomatic, plasma cells are up 10% or more of the blood cells in the bone marrow. M protein in blood is 3gm/dl. or more.

2. Solitary Plasmacytoma of the bone - a single tumor is present and no symptoms.

3. Extramedullary Plasmacytoma - plasma cell tumors develop in the upper airways, nose, nasal sinuses, larynx, GI tract, breasts and brain.

4. Bence Jones proteinuria or presence of light chains in urine.

5. Nonsecreting Myeloma.

6. Waldenstrom macroglobulinemia. Both B-cells and Plasma cells produce excess Macroglobulin. Various symptoms develop due to high blood viscosity from the excess macroglobulin.

7. Rare IgD and IgE myeloma. IgD myeloma is seen at relatively younger age. IgE myeloma is an aggressive type.

Diagnosis of MM:

A bone marrow biopsy is essential. MM diagnosis is made when the Plasma cell population is over 10%, usually at the time of diagnosis plasma cells are over 50%. Other positive findings are high microglobulin in blood and urine. Bone x-ray show lytic lesions and pancytopenia but these additional findings are not required for the diagnosis of MM.

Staging:

The international staging system categorizes MM into 3 stages based on blood tests:

Stage I. - Serum beta-2 microglobulin over 3.5 mg/L and serum albumin at/ over 3.5 g/dL. 

Stage II. serum levels are between the values of stage I and stage III.

Stage III. - Serum beta-2 microglobulin at or over 5.5 mg/L and high LDH (lactic dehydrogenase).

Revised International staging system (R-ISS):

Stage I. B-2 microglobin  < 3.5mg/L, albumin > 3.5d/L, no cytogenic abnormalities in iFISH (interphase fluorescence in situ hybridization).

Stage III. B-2 microglobin  >3.5 mg/L, High LDH, Presence of iFISH abnormalities. In MM the iFish cytogenic abnormalities are - deletion of 17p and/or t 4;14, and/or t 14;16. (p= short arm of chromosome 17. t=translocation of oncogene at 14;4 location).

Treatment of MM:

The current trend in the treatment of hematological malignancy is to perform Stem Cell Transplantation early. In MM the preferred age for stem cell transplant is below 75 yrs. Two different stem cell transplants are possible in MM. These are Autologous (patient's own stem cells) and Allogenic (HLA matched stem cells from the donors).

Targeted Therapy.

  - Proteasome inhibitor therapy. Proteasome is a protein that clears unused protein molecules from a dividing cell. If that clearing protein is blocked, then the dividing cells are choked with proteins and die. That is the basis of proteasome treatment. Drugs available are Bortezomib, Carfilzomib and Ixazomab.

- Monoclonal antibody therapy (mAb). The commonly use mAbs are Daratumumab for bone pain, Elotuzumab for accelerated killing by phagocytes.

- Histone Deacetylase (HDAC) inhibitors. These drugs block cell division. The available drug is Panobinostat.

- BCL-2 Inhibitor. Helps to kill cancer cells. Drugs available are Veneloclax.

Immunotherapy. Thalidomide accelerates the killing of rapidly dividing malignant cells. Derivatives of thalidomide are more powerful than thalidomide. Available drugs are Lenalidomide and Pomalidomide.

CART Therapy.  Surveillance T-cells have surface receptors by which T-cells attach to the foreign antigen. Because cancer cell antigen closely resembles the normal cell of the body, at times the receptors fail to bind with the cancer antigen. Mutated cancer cells have acquired this strategy and evade detection and death. In the CART therapy laboratory engineered Chimeric Antigen Receptors and T-cells from the patient are incubated together. These special T-cells are made to multiply in the laboratory and later transfused to patients to enhance tumor killing.

Chemotherapy. - A combination of 4 to 6 chemotherapeutic agents is administered in 4 to 6 cycles over 6 months to induce remission. Cyclophosphamide, Doxorubicin and Etoposide are commonly used in MM.

Treatment strategy for MM. - The first step is to induce remission through a combination of immunotherapy, targeted therapy and chemotherapy. The number of agents used in the combination varies according to the disease stage of patients. Then Watchful Waiting. Maintaining remission is usually achieved by immunotherapeutic agents.

If a recurrence of MM is detected, a Stem cell transplant is advised provided there is no contradiction.

Then again, a watchful waiting with maintenance therapy, and surveillance.

Prognosis:

The prognosis: Survival used to be 5 years for stage I, and for stage II and stage III rates were 3.5 yrs. and 2.5 yrs. respectively. In a 2021 publication, the 5-year survival rate was noted to be 75% in early cases, and in late diagnosed cases the rate was 48%.

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Pituitary Gland

 

                                                   Pituitary gland

                                                   PKGhatak, MD

The pituitary gland is a small endocrine gland, located at the base of the skull in the middle fossa and sits in the Sella turcica (Turkish saddle) of the sphenoid bone. The roof of the nose is just below it and is separated by a thin perforated bone partition called the cribriform plate, the hypothalamus and the optic chiasma are located just above the pituitary gland. The pituitary is positioned in between the eyes when projected on the surface. The pituitary is connected with the hypothalamus by a stalk consisting of nerve fibers and blood vessels. The frontal cortex overhangs in front of the pituitary.

The pituitary gland is two glands in one structure - the anterior pituitary and posterior pituitary. Both parts are endocrine in nature. The posterior pituitary is an extension of the hypothalamus. In between the two pituitaries are cells that form the pars intermedia.

Embryology of Pituitary.

The ectoderm cells of the developing roof of the mouth grow upwards in the form of a pouch -  Rathke's pouch. The neurons from the floor of the 3^rd ventricle of the brain extend down as an outgrowth to meet Rathke's pouch. These two sources make up the Pituitary gland – the anterior pituitary (adenohypophysis) originates from the cells of the roof of the mouth, the posterior pituitary (neurohypophysis) from the extension of the brain. The line of junction of these two parts contains cells and is known as Pars Intermedia. Pars intermedia is ultimately incorporated in the anterior pituitary and these cells produce MSH - melanocyte stimulating hormone. 

The pituitary gland is the conductor of an endocrine orchestra. The orchestra players are the adrenal glands, thyroid, thymus, pancreas, pineal, and testis/ovaries. The nerve center of this orchestra is the hypothalamus. Hypothalamus with its nerve fibers and the portal circulatory system sends signals to both pituitary glands. The hypothalamus is the headquarters of the autonomic nervous system. The hypothalamus acts as a bridge between the CNS and the endocrine systems 

Special Three:

The pituitary, hypothalamus and pineal have a closer relationship. The pineal gland produces melatonin, a hormone and through melatonin, the pineal maintains the circadian cycle, sleep, and waking rhythm. The pineal gland is considered the spiritual center and so called the 3^rd eye. These three structures (Pituitary, hypothalamus and pineal gland) working together are responsible for the control of heart rate, BP, appetite, body temperature, respiration, emotion and behavior, sexuality and fertility, growth of bones & muscles. skin color, water & electrolyte balance and health.

The hypothalamus communicates with the anterior pituitary by releasing hormones. Every anterior pituitary hormone is produced by a separate cell line; so, the hypothalamus has multiple releasing hormones.              Examples: ACTRH (adrenocorticotropic releasing hormone), TSRH, GHRH, etc. The nerve fibers from the hypothalamus send signals to release preformed hormones - ADH (antidiuretic hormone) and Oxytocin.

The hormone secretion from the pituitary gland is not continuous. Every 2 to 3 hours hormones are released in circulation.

Hormones of Anterior Pituitary:

Anterior pituitary gland hormones are ACTH (adrenocortical stimulating hormone).

 TSH (thyroid stimulating hormones).

 Gonadotropins- LH (luteinizing hormone), FSH (follicle stimulating hormone).

 MSH (Melanocyte stimulating hormone).

Posterior Pituitary hormones are. ADH (antidiuretic hormone) and Oxytocin.

ADH is produced by neurons of the hypothalamus and travels down the nerve fibers to the posterior pituitary and is stored in the vesicles. With the appropriate signal from the hypothalamus, ADH is secreted.

Oxytocin. Oxytocin is likewise produced by neurons of the posterior pituitary, travels to the posterior pituitary like ADH.

The pituitary gland may overproduce or fail to produce adequate quantities of the hormone. It also may develop tumors. Benign tumors of the anterior pituitary are the majority of tumors.

Table of Pituitary hormones.

Hormone	Target organ	Excess production	Deficiency
GH- growth hormone	Bones and muscular system.	Gigantism in children, Acromegaly in adults.	Dwarfism, Growth retardation. Osteoporosis, muscular weakness, depression.
ACTH	Adrenal cortex	Cushing disease	Addison's disease
TSH- thyroid stimulating hormone	Thyroid gland	Hyperthyroidism	Hypothyroidism
Gonadotropin LH- luteinizing hormone	Germ cells of the Ovaries/testicles		Failure to conceive if female. Low sperm count in males.
Gonadotropin FSH- follicle stimulating hormone	Interstitial cells of ovaries/testicles	Many adverse effects on estrogen excess and hyper testosterone, Blood clots, and an increase in hepatic and other tumors.	Few and scanty menstruation to amenorrhea in females. Erectile disorder in a male.
Prolactin	Breast both sexes	Lactation without pregnancy. Milk secretion in males	Lactation deficiency in postpartum..
MSH- melanocyte stimulating hormone	Melanocytes of the skin	Production of pigments of the skin and hair	Vitiligo and albinism
ADH- antidiuretic hormone	Kidney tubules	Fluid overload and hyponatremia	Dehydration and inappropriate production of dilute urine
Oxytocin	Pregnant Uterus	Rupture uterus	Failure of placental separation and poor uterine contraction during labor.

A few special Pituitary disorders.

Chromophobe Adenomas of Pituitary. Chromophobe adenoma of the pituitary is the most common adenoma and is a benign tumor. Pituitary adenoma does not secrete any hormone. and cells contain no granules, however, under the electron microscope, a few granules are detected. Symptoms of adenoma are related to increased internal pressure and hypofunction of the pituitary but symptoms vary because all different cell lines are not equally affected. Often the prolactin levels are high and ACTH, TSH and GH are lower.

MENS 1. Multiple endocrine neoplasia type one. Tumors of the anterior pituitary (mostly of prolactin producing cells) arise in association with tumors of parathyroid glands, pancreatic tumors – insulinomas and glucagonomas, and tumors of small intestinal hormone producing cells. The disease is inherited in an autosomal dominant pattern. Additional tumors of the adrenal gland, carcinoids, angiofibroma and meningiomas may be associated.

Sheehan syndrome. Massive postpartum bleeding leads to shock and pituitary necrosis. If patients survive the shock, then hypothyroidism, adrenal insufficiency, and menopause develop.

Empty Sella syndrome. The pituitary sits in a bony cup, only the top is covered by soft tissues. In benign intracranial hypertension, the persistent high CSF pressure produces gradual atrophy of the pituitary and symptoms of hypopituitarism develop.

Prolactinoma. Tumors of prolactin producing cells are either microscopic tumors or macroscopic large tumors- both are benign. Excess prolactin is associated with a deficiency of other anterior pituitary hormones. Symptoms of low cortisol and hypothyroidism are most manifested initially. Macrotumors produce increased CSF pressures, visual field defects, and eye muscles palsy in addition to hormonal changes.

Nelson syndrome. Following bilateral adrenal gland removal in Addison syndrome, the cells producing ACTH in the pituitary grow in excess and form a tumor. Besides Cushnoid features, various visual symptoms and blindness may develop.

Craniopharyngioma. Craniopharyngiomas are benign cysts and occasionally solid adenomas developed from the remnant cells of Rathke's pouch. Symptoms are increased intracranial pressure and visual field defects. This entity is a childhood malady and is occasionally seen in adults.

Rathkes cleft cysts. Cysts develop in the remnant Rathke's pouch. The presentation is very similar to craniopharyngioma.

Lymphocytic hypophysitis. This entity is a rare complication seen in late pregnancy or early postpartum. It is an autoimmune disease with lymphocytic infiltration of the pituitary gland and results in various degrees of hypofunction of the pituitary. The cause is unknown, IgG4 and IgG1 antibodies were detected by some investigators pointing to heterogenic sources of antigen.

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Appendix

 

                                                             Appendix

                                                         PKGhatak, MD

Appendix means an attachment to a document. Centuries earlier when Geeks began to dissect cadavers to study human anatomy, they described a small narrow tube hanging from the cecum and called it an appendix. Appendix later received a nastier name in 1579 given by Yolanda Smith - Vermiform appendix (worm like appendix) and that name got tucked in the medical field.

 ..Before the days of general anesthesia and sterilization, infection of the appendix was bad news as bad as a death sentence. In 1735, Dr. Claudius Amyland in London, England successfully surgically removed an appendix from an 11-year-old. boy who had swallowed a needle that perforated his appendix and lodged in the scrotum.

..In the Journal of Evolution Biology H.F Smith et al described that Appendix evolved twice in the animal kingdom, the latest appearance was in marsupials. The appendix has largely disappeared from the animal kingdom and now the appendix is found only in humans, primates, rabbits, prehensile tailed porcupines, flying squirrels, meadow voles and wombats.

..There are wide variations in the anatomy of the cecum and appendix in mammals – some have only multi chambered cecum and appendix and no small bowels, some have a larger appendix and small cecum, and some only appendix and no cecum.

..Human appendix in adults is about 3 inches long, attached to the far end of the cecum next to the junction of the small intestine to the cecum. The appendix is richly supplied by arterial blood. The size of the appendix is much larger in the developing fetus and continues to grow through early childhood and starts to diminish in size with the onset of sex hormones secretion.

..A microscopic look at the appendix will convince anyone that the appendix belongs to the lymphatic system. The lymph follicles of the appendix are large compared to the rest of the tissues, the follicles are many and arranged in a circle. Structurally the appendicular lymph follicles resemble Peyer's patches of the small intestine and functionally perform like the thymus gland. In fact, calling the appendix the intestinal thymus is not that far off.

In the appendix, lymph follicles contain lymphocyte B-cells and T-cells. B-cells and T-cells communicate with each other and function like T & B-cells in any other tissue. The bacterial antigen and other antigens are identified and collected by T-cells then given to B-cells. Cytokines of T-cells act on lymph follicles and produce immunoglobulin IgA. IgA is the immunological defense of the GI tract and prevents the invasion of bacteria, fungi, viruses, and toxins. IgA is also produced in the lymphatic tissues of the rest of the intestine.

.. Besides immunological functions, the appendix is the home of beneficial bacteria in the large gut. When diarrheal diseases and the use of antibiotics wipe away the gut bacteria and the overgrowth of harmful bacteria produce illness, the appendix replenishes new batches of beneficial bacteria.

..In reconstructive surgery, the appendix is utilized and fashioned as a sphincter of a newly created urinary bladder out of a section of the gut and also use appendix as the replacement part of a removed ureter.

..In earlier days the appendix of ruminant animals was considered a storehouse of fermenting bacteria and that belief led Charles Darwin to consider the human appendix as a relic of leaf-eating humans.

..The incidence of appendicitis is about 1 million a year in the USA. The mortality rate is 0.3%. Today, the diagnosis of acute appendicitis is made easier by Ultrasound studies. A swollen appendix and local peritoneal ascites (fluid collection) mean acute appendicitis. In retrocecal appendicitis or in ectopic pregnancy an MRI is referable. Elucidating one finger tenderness at the McBurney and leukocytosis with a left shift are not solely relied upon, but are important clinical findings.

A recent trend in appendicitis treatment is the use of antibiotics alone, no surgery, and careful watch, provided ultrasound study does not show fluid collection.

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Color of Urine.

 

                                                        Color of Urine

                                               PKGhatak, MD

The normal color of urine is pale yellow. The hemoglobin breakdown product bilirubin is excreted by the liver in the bile. Most of the bilirubin is eliminated from the body in the stool, some 20 % is reabsorbed and filtered by the kidneys. In the urine it appears an urobilirubin and that colors the urine.

..Dehydration produces dark yellow color urine; pale urine is produced from drinking several glasses of beer. Urine color becomes barely noticeable or absent in common bile duct obstruction from impacted gall stones or pancreatic cancer.

..Consuming beetroot, carrots, and blackberries makes urine red and various shades of yellow. Green urine is likewise seen after eating asparagus. In the summer months, eating ice shavings with colored syrup and colored ice cream can give a variety of colored urine.

..People taking prescription medications, if they read the printed information given by the pharmacy, will find certain pills may discolor the urine.

 Drugs producing colored urine: -

..Orange color – Rifampin and other Rifampin derivatives, Sulfadiazine, Senna. Warfarin, Phenazopyridine.

..Pink color – Phenolphthalein, Vitamin B12, Senna.

..Brown color – Nitrofurantoin, Metronidazole, chloroquine.

 .Black color – Sorbitol, Methyldopa.

..Blue color – IV methylene blue. Indigo carmine.

..Green color – Promethazine, cimetidine, Amitriptyline, Indocin, Metoclopramide.

 Diseases producing colored urine: - Red urine. - Bleeding from the urinary bladder, kidneys and urinary tract due to stones, tumors, tuberculosis and trauma, including surgery.

..Brown urine. - Free hemoglobin and myoglobin (hemoglobin of skeletal muscles) in the urine. This may arise from crush injuries, Rhabdomyolysis. Prolonged march. Electric shock, Seizures. Massive pulmonary infarction and Intravascular hemolysis. Only a few important intramuscular hemolytic causes are mentioned here.

..Hemolytic anemia is classified as I. Inherited and II. Acquired.

 I. Inherited intravascular hemolysis due to 1. abnormal cell shape and size e.g. Thalassemia, Sickle cell anemia, Hereditary spherocytosis. Elliptocytosis.        2. Enzyme deficiency. G6PD (glucose 6 phosphatase deficiency) PKD (pyruvate kinase deficiency).

II Acquired hemolytic anemia. Burns. Autoantibodies –1. Immune hemolytic e.g., CLL (chronic lymphatic leukemia) Non-Hodgkin lymphoma. 2. Autoimmune hemolytic e.g., minor blood group, Lupus erythematosus. 3. Autoimmune hemolytic e.g., post transfusion hemolysis, Hydrops fetalis and hemolytic anemia in newborn – Rh negative mother sensitized by Rh positive baby during pregnancy, mother's antibodies cross the placenta and hemolyze fetal RBCs of the subsequent pregnancy. 4. Drug induced antibodies e.g., Penicillin, Cephalosporins, Levofloxacin, NSADS, Methyldopa, Nitrofurantoin. 5. Mechanical causes- e.g. RBC breaks down in the microcirculation e.g., TTP (thrombotic thrombocytopenic purpura). ITTP (idiopathic thrombocytopenic purpura. Mechanical cardiac valves. 6. Miscellaneous e.g., PNH (paroxysmal nocturnal hemoglobinuria.

Hemolysis is due to the presence of antibodies. e.g., Cold agglutinins in mycoplasma pneumonia.

.. Bacterial hemolysins – cholera toxin, Clostridium perfriengence (gas gangrene, CMV, Rickettsia, Brucella, Trypanosoma, EBV (Epstein Barr virus).

 Autoimmune hemolytic anemia. Paroxysmal nocturnal hemolysis. Mediterranean fever.

..Other causes – Acute renal tubular necrosis. Acute glomerulonephritis, Good Pasture syndrome, snake bite, CO poisoning, barbiturate poisoning, polymyositis. muscular dystrophy, McArdle syndrome.

 ..Intracellular Parasites- Malaria, Babesia, Trypanosoma.

.. Black urine: Malignant melanoma.

..White urine. Lymphatic obstruction. Fungal UTI. Cellular derbies from TB.

. Snowflake urine. Calcium phosphate crystals.

. White cloud in oxalosis.

. Standing urine open to air changing to dark or black due to Alkaptonuria.

.. Spurious color changes – red diaper syndrome due to growth of bacteria Serratia marcescens.

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Sarcoidosis.

 

                                                                     Sarcoidosis

                                                         PKGhatak, MD

In the old days of pulmonary tuberculosis, sarcoidosis was an interesting entity and entered into the differential diagnosis of pulmonary tuberculosis. Nowadays, sarcoidosis has taken that spot in the differential diagnosis of granulomatous diseases. This distinction is applied to sarcoidosis because the cause of sarcoidosis is unknown, it can and usually affect multiple organs. Sarcoidosis may be self-limited, progressive or chronic. Sarcoidosis passes through three stages – inflammation, granuloma formation, fibrosis. Many other diseases have similar pathological characteristics. In short, sarcoidosis is diagnosed when all known causes of a granulomatous disease are eliminated.

Granuloma is a tiny localized collection of densely packed immune cells, mostly macrophages, and epithelioid cells (elongated nucleus of macrophages), and a few Langhans giant cells (fusion of macrophages) surrounded by a zone of lymphocytes, eosinophils with some fibrosis at the periphery. The distinctive features of sarcoid granuloma are asteroid body, an eosinophilic star shaped structure, and rounded laminated partially calcified structures called Schaumann bodies. The foreign-body granuloma at the center of the granuloma contains a part of the foreign body. Sarcoid granuloma is described as Non-Caseating granuloma. In the case of tuberculosis, the bacterial toxin causes the death of cells and matted dead cells are called caseation.

Sarcoidosis is due to the response of the Immunocytes to foreign agents/antigens. But the identity of the antigen and mechanism of the derailed function of the Immune cells are not known. The hallmark of sarcoid is a granuloma. Immune cells fail to destroy the foreign antigen but contain it locally by forming a dense cellular wall around it.

 Common granulomatous diseases:

Foreign body – wood splinters, metal fragments, insect stings, spider bites. The ingrown root of the hair, tattoo ink, inhaled beryllium, dermal fillers collagen, forgotten sutures, aspiration of food particles in the lung.

Granulomatous polyangiitis or Wagner granulomas. - granuloma forms in the nasal passage, trachea, major bronchi. Hemoptysis is the presenting symptom.

Eosinophilic polyangiitis also called Churg-Struss syndrome, Necrotizing vasculitis of small and medium size vessels with peripheral eosinophilia and ANCA positive vasculitis. Patients present with asthma, weight loss and polyneuritis, bronchitis and other systemic symptoms.

Crohn's disease –  A chronic granulomas ulcerative lesion of the colon and terminal ilium and anal canal.

Rheumatic fever. Streptococcal antigen triggers granulomas on heart valves.

Rheumatoid arthritis. It is a debilitating chronic arthritis of the small joints of fingers, cervical spine, and knees; occasional granulomas in pleura and pulmonary fibrosis.

Mycobacteria infection. - Pulmonary tuberculosis, non-MT granulomatous diseases, Leprosy.

Bacterial. - Cat- scratch fever, Listeriosis,

Fungus. - Histoplasma, coccidioidomycosis, blastomycosis, Cryptococcus.

Parasites. -Leishmaniosis of skin, liver and spleen; pneumocystis.

Symptoms of sarcoidosis are variable based on organ involvement:

Pulmonary lesions are 

1. Hilar adenopathy in young adults must be differentiated from sarcoma by CT scan of the chest and abdomen and mediastinoscopy biopsy.

2. Pulmonary infiltrates with or without adenopathy resembling pulmonary tuberculosis. Interferon gamma release assay, sputum smear and cultures for AFB and rarely bronchoscopic biopsy may be required. 3. Cavitary pulmonary lesion presented with hemoptysis. 4. Extensive pulmonary fibrosis and loss of lung tissue.

Skin: Lesions are.

 1. Lupus pernio. - Disfiguring lesions of nose, cheeks, lips

.2. Granuloma annulare - flesh colored raised skin lesions on bony prominences and characterized by multiple rings. 

3. Polyarteritis nodosa. - Raised painful nodules, purplish blue color, appear in crops on the lower legs over the shin bones.

Heart. Heart block and other conduction abnormalities. Diagnosis is difficult if only a heart block is present. Liver biopsy is often diagnostic.

Eye. - Uveitis, chorioretinitis, sclerites, blindness. Dry eyes. Lachrymal gland biopsy may be required.

CNS. Facial nerve palsy is also called Bell's palsy, various neurological symptoms based on stages of the disease of CNS. Meningitis, seizures, dementia, polyneuropathy.

Kidneys. Recurrent renal stones.

Bones. Osteoporosis.

Blood. High calcium and markedly raised ACE (angiotensin converting enzyme), high ACE is also present in other granulomas but usually in the modest range. ACE is produced by granuloma cells.

Common symptoms at the time of presentation. The symptoms vary according to the organ involved. In the young adult male, hilar lymphadenopathy is usual. In general, the condition resolves spontaneously in 6 weeks. Recurrent skin lesions are common in blacks. Various eye lesions maybe not be so obvious initially but in chronic lesions, the eye involvement is usual. Dry eyes may require a biopsy of lacrimal glands for a diagnosis. Cavitary and progressive pulmonary fibrosis have a poor prognosis.

Treatment:

Treatment is urgent when eyes, heart, CNS sarcoid lesions are present. Hypercalcemia may require emergency medical therapy.

Prednisone is the primary drug. Because of major side effects, Methotrexate, Leflunomide, Hydroxychloroquine, Imuran, and cytotoxic drugs are added while the dose of prednisone is decreased or stopped.

Prognosis: Asymptomatic hilar lymphadenopathy has the best prognosis. Processive fibrosis has the worst outcome.

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Thymus

                                                        Thymus

                                            PKGhatak, MD

In adults, the Thymus gland exists only in name; from the newborn to childhood, till the onset of puberty, the thymus, sitting in front of the heart, dominates. The thymus in children is the largest gland in the chest. The Greeks thought it was the center of anger and named it thymus. The thymus name was derived from thumos meaning anger. Galen was the first physician who correctly described the evolution of the thymus in childhood and greatly reduced in size in adults. In adults, the thymus produces only a few mature   T-cells throughout life.

The thymus grows from the third and fourth pharyngeal pouches, one on each side. As the two lobes of the thymus grow, the cavities in the stalk are closed off and only a vestige remains. The developing thymus lobes descend in the thorax and move close together towards the center and finally join together as one thymus gland.

Several genes encode the development and maturation of the thymus. Deletion of chromosome 22 results in absence of the thymus and clinically the condition is known as DiGeorge syndrome. This syndrome is incompatible with life beyond a few weeks after birth.

Unlike the pancreas and liver, the thymus is just one gland - an endocrine gland. It secretes Thymosin and other hormones. The task of the thymus is to train the immature lymphocytes to become super sleuths like FBI agents. That task has two aspects - a Positive Selection, is the ability to detect any antigen that is foreign to the human body, and the other is a Negative Selection that ensures the quality is not to make a mistake and call normal body antigens as foreign agents. The positive section is delineated by the presence of specific receptors on the T cells surface that have the ability to recognize MHC immune antigen. MHC stands for major histocompatibility complex. Once the lymphocytes are trained properly, they are released into circulation with an official T-Cell designation. T-cells (thymic lymphocytes) take residence in lymph nodes, the spleen and move around the body in the blood. T-cells are further differentiated in CD (cluster differentiation) grouping based on the presence of cell surface proteins. Out of this classification, the CD4 and CD8 T-cells are well known since HIV/AIDs became prevalent. This acquired quality is called the Adaptive Immune System as opposed to Innate immunity, as for example, the macrophages engulf bacteria.

There is a complex relationship between Testosterone and gut bacterial antigen in the development of Positive and Negative Senses. Testosterone modifies gut bacterial antigen that elevates negative sense, whereas Estrogen suppresses negative sense. XX chromosome in females and the master gene AIRE gene (Autoimmune regulator) regulate gene expression that codes autoimmunity are active participants in this process.

 Structure of Thymus.

Each thymus gland has an outer zone of densely packed cells called the cortex and a loose collection of cells in the inner zone called the medulla. Each lobe is made up of several lobules.

The cells of the cortex are mostly thymocytes - newly arrived lymphocytes from the bone marrow waiting to be turned into T-cells. The epithelial cells in the cortex are arranged as a fine network of cells supporting the thymocytes. In the cortex, the thymocytes acquire positive selection.

The medulla has a rough distribution of epithelial cells and fewer thymocytes and collections of whorls of epithelial cell remnants from the stock of the third pouch. These whorls are distinct microscopic features of the thymus and are known as Hassall's corpuscles. In the medulla, the thymocytes acquire negative selection.

 Hormones and Cytokines of Thymus:

Thymosin, Thymulin and Thymopoietin are three secretory hormones of the thymus. The first two are involved in T-cell transformation and the thymopoietin helps to keep the mature T-cells to keep up the acquired adaptive immune property. The cytokines are interleukin class IL-1, IL-6, GM-CSF, zinc- thymulin complex and other polypeptides.

 Diseases associated with Thymus gland disorder:

Myasthenia gravis. In thymoma or hyperplasia of the thymus the T- cell functions are derailed. The body develops antibodies to Acetylcholine receptors. Lack of action of acetylcholine is felt as facial muscle weakness, weakness of legs and fatigue.

 DiGeorge syndrome: Deletion of chromosome 22 results in a congenital abnormality of the heart, hair lip and cleft palate, esophageal tracheal fistula, absence of Thymus gland and total failure of adaptive immunity of T-cells. If the condition is recognized early in infants Thymus gland transplant is indicated.

SCID: Severe combined immunodeficiency disease. This results from the deficient maturation of hemopoietic progenitor cells. T-cells, B-cells, NK (natural killer) cells are deficient.

Autoimmune endocrine syndrome: In this syndrome, T-cells fail to acquire the Negative Selection knowledge while developing in the medulla of the thymus. Thyroid, Parathyroid, and Adrenal cortex are destroyed due to autoantibodies and hormones from these endocrine glands become deficient. Candida infection of the mouth and GI tract is also a common feature of this entity.

Thymoma is associated with multiorgan autoimmunity. In this disorder, thymus growth disturbs the normal development of T-cells. The disease resembles Graft vs Host Disease.

The thymus gland is damaged by radiation of the chest and chemotherapy for cancer. Regeneration of the thymus is possible, shown recently in experimental animals. The CCL11 cells of the damaged thymus stroma initiate the recruitment of peripheral Eosinophils. The natural killer cells and Th2 cells inter-react with eosinophils and restoration of structure and functions resume.

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Liver

Liver

PKGhatak, MD

The liver is an amazing organ. It is the largest solid abdominal organ but hardly noticed. The liver is tucked away underneath the dome of the diaphragm and surrounded by a rib cage. Doctors want to examine the liver have to make it descend down with breathing (breathing out) by asking patients to breathe deep in and out and pushing his/her fingers deep underneath the right side of the rib cage. If the liver is palpable a normal liver is like the relaxed bicep muscle, a cirrhotic liver feels like ear cartilage.

The liver is the largest chemical factory of the body. It gets its raw materials from the GI tract, the digested food and drinks via the portal veins. Then the liver manufactures proteins, fat, cholesterol, glycogen from sugar and glucose from amino acids and fatty acids, hormones, enzymes, and other various chemicals; filters the waste products, detoxifies, absorbs toxins, and then releases these substances at the appropriate time in the blood. The liver is an endocrine cum exocrine gland and much more.

Embryology of Liver:

Liver growth starts early, as early as 2 weeks following fertilization of the ovum. An invagination of endoderm of the foregut, close to the Septum Trasvestum, occurs and that becomes the site of liver development. A liver bud develops and the cells of the head end of the liver bud start to grow in an empty space reserved for the heart and blood vessels. The developing cells destined to be liver cells grow like finger projections and orient in alternating rows with the endothelium of the blood vessels which later become the terminal capillary branches of the portal vein. The septum trasvestum becomes the capsule of the liver and fibrous tissues from the capsule enter the developing liver cells and become the scaffolding and provide stability of the liver. The tail end of the same liver bud forms the gall bladder and extrahepatic bile ducts.

Liver lobule:

The liver is a mixture of the exocrine gland, endocrine gland, vascular organ and storehouse of many things including every Stem Cell line.

The structural and functional unit of the liver is a lobule – a tiny acinus. The total number of lobules in a liver is estimated to be 300 billion. An understanding of microscopic anatomy is essential to study the physiology of the liver.

A liver lobule is a three dimensional unit. It looks hexagonal under the microscope but in a living state, a lobule is more or less like a circular structure. At the periphery, there is an arcade formed by a branch of the portal vein. Straight branches, the venules of the portal vein – often referred as a lake, originate from the arcade and travel toward the center of the lobule and converse on a central vein. The appearance resembles the spokes of a wheel. Columns of liver cells follow closely the straight portal venules. The other side of the liver cells column is a draining tube – a tiny bile duct. This pattern is repeated in all lobules. The interlobar space is interlaced with fine fibrous tissues attached to the liver capsule. This space contains branches of the hepatic artery and lymph vessels and various mesenchymal cells, including the well known Kupffer's cells.

Branches of the hepatic artery, bile duct and lymphatics follow the branches of the portal vein. a hepatic artery branch to the lobule opens into the lake. The plexus of fine branches of the hepatic artery supplies all the cells of the bile duct and other structures in a lobule. The central vein joins with adjoining veins and ultimately forms 2 to 4 Hepatic veins and hepatic veins terminate in the Superior Vena Cava.

In essence, each hepatic cell is bathed by the blood that is a mixture of arterial blood and venous blood returning from the GI tract. Intrahepatic bile ducts are as profuse as blood vessels are and lobules are drained continuously.

A Hepatocyte:

A liver cell is a large cell and rich in the cytoplasm and nuclear materials. The nucleus is surrounded by a well demarcated nuclear wall. The nuclear chromatin is very prominent and generally contains two nucleoli. The cytoplasm is loaded with mitochondria, smooth and rough endoplasmic reticulum, Golgi apparatus, lysosome, peroxisome, inclusion bodies, stored glycogen, and lipid molecules.

Blood supply: The liver is a very vascular organ. It weighs just 2 % of the body weight but gets 25 % of cardiac output. Of the total blood inside the liver, 75 % is from the portal vein, and the rest is arterial. The liver stores 15 % of total body blood and in hemorrhage, hepatic blood is made available.

Bile secretion: In a day about 1 liter of bile is produced. Bile is produced continuously and finds its way to the gall bladder first and is stored there. After a fatty meal gall bladder discharges bile into the intestine.

Liver Function: It is said that the liver completes 500 different tasks.

The following are just to name some of these functions.

Metabolism of Carbohydrate: Every aspect of carbohydrate metabolic processes from energy production, breakdown of glycogen, making glucose from fat and amino acids and conjugation of the carbohydrate moiety to toxic substances take place in the liver.

Fat metabolism: Cholesterol is synthesized in the liver. The liver converts fatty acid to fat molecules and breaks down fat and releases fatty acid in starved conditions.

Protein synthesis: Albumin and ferritin are made in the liver, so also all the transport proteins - just too many to mention here.

Acute phase positive proteins are about 30 in number. Some important are C- reactive protein, procalcitonin, alpha antitrypsin, heptidine,  IL-1 receptor antagonist, D- dimer. The negative acute phase proteins are albumin, transferrin, transthyretin. 

Blood coagulation: Several anticoagulants and clotting factors are made in the liver. Anticoagulants are protein S and protein C, Antithrombin. Coagulants are fibrinogen, prothrombin, factors- V, VII, IX, X, XI, XII. Von Willebrand and factor VIII are made in the liver but not by the hepatocytes.

Hormone production: Thrombopoietin, Somatomedin, Angiotensinogen, Hepcidin.

Vitamins production: Vitamin D 25-OH. The liver acts as a store of fat-soluble vitamins- A, D, E, K. and B12.

Storage function: Iron, Glycogen, fat, copper.

Detoxification: Most toxins are made less toxic or harmless by conjugation wand made sulfate, glucuronide and simply converted to inert substances.

Execratory function: Bile acids and bilirubin.

Digestive function: Bile acids and bicarbonates.

Myeloid Metaplasia and liver: Several hematological conditions end up destroying bone marrow and replaced it with fibrous tissue, a condition known as myelofibrosis. In such conditions liver and spleen attempt to generate deficient blood cells.

Regenerative power: The liver carries all stem lines. At little as 15 % of the liver remaining from an accident or liver donation, the remaining liver will regenerate to the normal size.

Liver transplant began in 1967, it has become an essential operation in congenital biliary atresia. A liver transplant is performed for liver failure due to many causes including alcoholic cirrhosis and viral hepatitis C.

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Pancreas

                                                            Pancreas

                                              PKGhatak, MD

The pancreas is an important organ but not essential to life since the isolation and purification of Insulin in 1921 by Dr. Banting and a medical student Mr. Best. The pancreas is a mixed gland contains both exocrine (secretion by duct) and endocrine (secretion directly enters blood) glands.

Development of Pancreas:

The pancreas has two sources of origin. Two independent buds develop from the foregut endoderm - one dorsal bud and one ventral bud, at the junction of the foregut and midgut, next to the origin of the biliary bud. The dorsal bud produces the major part of the gland and the main duct, the ventral bud produces a part of the head, the uncinate process and the accessory duct.

Exocrine development:

In the beginning, the primitive pancreatic cells differentiate into the acinar cell line (gland with ducts) and the endocrine cell line. Each acinar duct joins with the adjoining acini and ultimately forms two major ducts as mentioned above. Each acinar duct joins with the adjoining acini and ultimately forms two major ducts as mentioned above. The main pancreatic duct opens into the 2nd part of the duodenum and the duct is a bit dilated, called the ampulla of Vater and is surrounded by smooth muscle sphincter, the sphincter of Oddi. The common bile duct joins the pancreatic duct in the ampulla and the opening in the pancreatic duct is guarded by the sphincter of Boyden. The accessory pancreatic duct opens just proximal to the bile duct + pancreatic duct opening. In adults, many congenital anatomical variations of pancreatic ducts and the occasional head of the pancreas are encountered during surgery.

Endocrine Development:

The developing endocrine cells are grouped together in several clusters and are widely dispersed all through the gland. These clusters are called Langerhans Islands. Endocrine cell populations are further divided into alpha, beta, delta and C cells. All these cells are present on every island. Initial tiny ducts are attached to each islet but soon the ducts disappear.

Location of Pancreas:

The pancreas is located deep inside the abdomen on the posterior abdominal wall, behind the peritoneum. It is firmly anchored on the wall; the head of the pancreas fills the c-shaped space of the duodenal curvature, the main body lies across the abdominal wall, the tail part almost touching the spleen. In front of the pancreas is the Lesser Sac of the Omentum, the stomach slides over it easily.

Exocrine Function of Pancreas:

Pancreatic enzymes are secreted by acini cells and are rich in digestive enzymes -

Pancreatic Amylase, Trypsin, Chymotrypsin, Lipase, Phospholipase, Cholesterol esterase. In addition, the ductal cells secrete Chloride and Bicarbonate.

The total volume of pancreatic secretion is 2 to 3 liters. a day.

The pancreatic juice is very alkaline and acts with bile to neutralize highly acidic gastric discharge in the duodenum.

The action of Pancreatic enzymes on Food:

As the names imply, the amylase digests complex carbohydrates into glucose, trypsin and chymotrypsin digest proteins into simple amino acids and Lipase digest fat into fatty acid and glycerol, cholesterol ester breaks down cholesterol. In the digestive process, duodenal enzymes play a significant part also.

Endocrine Function of Pancreas:

Alpha cells secrete Glucagon.

Beta cells secrete Insulin and Amylin.

Delta cells secrete Somatotropin, Ghrelin and Pancreatic polypeptides. Gastrin is secreted in an early stage of development and later, the stomach secretes gastrin exclusively.

 The C-cell function is not known.

The action of Glucagon. Glucagon breaks down glycogen stores in the liver and skeletal muscles. It stimulates amino acid conversion to glucose (neogluconogenesis). Glycogen turns fatty acids into fat molecules in the liver. Glucagon delays the release of Insulin from the pancreas.

The action of Insulin.  Insulin binds with insulin receptors present on the surface of every cell. A protein molecule GLUT4(glucose transporter 4) comes up to the surface of the cells and an Insulin molecule bound to the receptor fuses with the membrane. This opens up channels for glucose molecules to enter the inside of the cell. The glucose molecule is immediately converted to glucose phosphate by the enzyme phosphatase. This keeps the concentration gradient in favor of glucose crossing inside the cells. Insulin favors glycogen synthesis, the conversion of fatty acids to fat molecules and amino acids to protein. Insulin promotes body growth and increases growth hormone secretion from the pituitary gland. Insulin delays glucagon secretion and thereby reduces glycogen breakdown.

The action of Somatostatin. Somatostatin is a gastrointestinal motility inhibitor. Somatostatin decreases both exocrine and endocrine secretion of the pancreas, decreases secretions from the duodenal and small intestinal glands. It reduces growth hormone release from the pituitary gland. It reduces gastric motility, gastric acid and gastrin secretion.

The action of pancreatic polypeptides. These small molecules suppress pancreatic exocrine secretion, gall bladder contraction and gastric motility.

The action of Ghrelin. Ghrelin promotes growth hormone release, muscle growth, and increases appetite. 

Blood Supply of Pancreas: Pancreas is richly supplied by arterial circulation. Celiac artery and Superior mesenteric artery supply arterial blood. The venous drainage goes to the liver by the Portal vein.

Insulin sensor: The alpha and beta cells act as the sensor of blood glucose levels. Alfa cells modify glucagon release by a negative feedback loop; whereas the beta cells release more insulin when sugar levels are high and shunt down Insulin release when the sugar level is low.

Nerve Supply of Pancreas. Like every abdominal organ, the pancreas has two nervous systems innervation - namely Somatic and Autonomic nervous systems. Nerve fibers going in and out of the pancreas pass through the celiac ganglion but many fibers just pass through.

Somatic sensory. The nerve cells are located in the Dorsal Root Ganglia (DRG) of the spinal nerves T 6 to L 2. The nerve fibers carrying the pain and other sensations enter the spinal cord and travel along the intermediate lateral tract of the spinal cord to the nuclei of the Thalamus. The 2nd order neurons from the thalamus cross the midline to reach the cerebral cortex. The DRG is sensitive to Capsaicin, CGRP (calcitonin gene related peptide). The neurons generate substance P.

Motor division.  The main center for secretary and contractile functions is located in the Nodosa Ganglion of the Vegas nerve. The axions from these neurons directly innervate all the cells of the pancreas.

Autonomic Nervous System:

Sympathetic supply. The nerve cells are located in the Celiac ganglion, the Mesenteric ganglia, and the Paravertebral ganglia. The alpha fibers of sympathetic nerves produce vasoconstriction, delay secretion and decrease endocrine function. Beta fibers stimulate Insulin and glucagon production and release.

Parasympathetic Nervous System:

The nerve cells are located in the Dorsal ganglia of the Vegas nerve. The axon of these nerves makes connections with the neuron present in the pancreas itself. Parasympathetic stimulation increases both exocrine and endocrine secretion and production.

Neurotransmitters:

Somatic nerves are Cholinergic. Sympathetic nerves are noradrenergic, glycinergic, and respond by releasing Neuropeptide gamma. Parasympathetic nerves are nicotinic-cholinergic at the ganglia and muscarine choline at the postganglionic terminal fibers.

The pancreas is fully developed at birth but only the exocrine function is present at birth. At about 15 weeks of life, the endocrine function begins.

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Bronchogenic Cysts.

 

                                                        Bronchogenic Cysts

                                                   PKGhatak, MD

Bronchogenic cysts are rare in adults but not so uncommon in newborns and young children. In a 3 to 6 week old fetus, two independent lateral lung buds develop as outpouchings from the ventral wall of the primitive foregut. (1).  Each of these two lateral buds differentiates as right and left main bronchi. The primitive foregut differentiates into the trachea and esophagus by developing a deep groove and joining the laryngotracheal sulci of the lateral wall of the foregut. Each main bronchi rapidly grows in the surrounding mesenchymal tissue and branches repeatedly and forms the rest of the conductive airways. Bronchogenic cysts arise from the development errors of the bronchogenic cells. Some of the bronchogenic cells remain attached to the developing foregut and that is the reason the bronchogenic cysts appear outside the thorax as these cells form cysts.

The bronchogenic cyst develops as a small solid mass and then as proteinous mucus begins to accumulate and it takes a cystic appearance. The walls of the cysts are thin and cysts have no ducts. As the cyst enlarges it compresses the adjoining structures - trachea, bronchi, and blood vessels in the middle mediastinum. Symptoms vary from being totally asymptomatic to cardiopulmonary compromise.

 Incidence: one in 50,000 hospital admissions. Location: 10 % of bronchogenic cysts are located in the middle mediastinum. The mediastinal cysts account for 50 % of all lung cysts and are seen in the paratracheal, carinal, para-esophageal and hilar region. 20 % of bronchogenic cysts are intrapulmonary and develop late and are seen in adults. Other locations are the neck, pericardial, pleural, diaphragm, and retroperitoneal. Size of the cysts: 2 to 10 cm in diameter, usually single.

Cysts are lined with ciliated pseudostratified columnar respiratory epithelium and squamous metaplasia is rarely present. In addition to mucus glands, cartilage, smooth muscle and blood may be present.

 Symptoms in children: Stridor, shortness of breath, dysphagia, superior vena cava syndrome, pneumothorax and pneumonia. In adults: Most cysts are asymptomatic and detected in chest x-rays, and recurrent pneumonia.

 Complications: Fistula formation in the tracheobronchial tree, malignancy. Diagnosis: The present generation of sonograms is very sensitive and can detect bronchogenic cysts in utero. In newborns to adults, the chest x-ray and CT scan detect all bronchogenic cysts, rarely MRI is needed.

Treatment: Surgery is the only option in symptomatic cases and in adults, lobectomy is usually required for intrapulmonary cysts. Surgery is also recommended for asymptomatic cysts before the start of complications.

Reference: 1.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5320013/

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