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 Systemic Circulatory System. The lesser circulatory system consists of the right atrium, right ventricle and pulmonary artery and its branches to 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, have 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, 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 Endothelin to its receptors and blunt 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 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 neither risk factors are known; 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 in people under 35 yrs. 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 rare 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 chromatins 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 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 Dendritic cells. Activated B-cells in lymph nodes survive only 4-5 days. Some activated B-cells move to 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 tissue/organ.

Effects of Uncontrolled growth of Plasma cells.

Rapidly multiplying plasma cells displace other blood forming cells, and soon plasma cells number grow to 60 to 80 % of 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 in 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 acutely. 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 spleens 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 -  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 in between 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 hematology 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 Deacetlase (HDAC) inhibitors. These drugs block cell division. The available drug is Panobinostat.

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