Septicemia and Sepsis

 

Septicemia and Sepsis:

P.K. Ghatak, MD

These two terms are often used interchangeably but they do not covey the same meaning. Septicemia means tissue damages from blood-borne pathogens – primarily bacteria or viruses. Sepsis indicates tissue damages from released of Cytokines, TNF and inflammatory Interleukins from the accumulated blood cells and immunocytes at the site of infection.

Septicemia:

Whenever a harmful agent gets inside the body, the body tries to put a barrier around it so that the harmful agent does not spread to other parts of the body. But due to a number of reasons, this may fail. And if the agent a biological agent, it invades tissues widely and enter the blood stream. The presence of live biological pathogen and damage produce by its toxins is called septicemia.

Our body is pre-programmed to repose by a set pattern of actions called 1. Innate or inherited immune reaction. 2. And by a separate set of actions, from experience gained from encounters with the offending agents, called Acquired Immune reaction.

1 Innate reaction :

The skin, surface layer of the nose, mouth, GI, Respiratory and Genitourinary tracts are the physical barriers to invaders. Once that defense is breached, then the responsibilities fall on the surveillance cells for finding the invaders by the immune cells called Dendritic cells. Dendritic cells recognize the molecular patterns of the invaders' surface membrane, and the dendritic cells attach themselves to it, like a key fits a lock. Then, these immune cells release chemicals, called Cytokines. In repose to cytokines, neutrophils, monocytes, eosinophils, phagocytes and complements (present in plasma) gather at the site. And a series of actions and reactions take place in the local area resulting in increased blood flow, redness, swelling, temperature elevation and temporary loss of function.

This is called, Classical Pathway. Other paths are - Alternate Pathway and Mannose-Lectin Pathway. These pathways are activated when the invaders are yeasts, viruses and certain other groups of bacteria.

The end result of all pathways are that the same. The invasion is checked, the invaders are paralyzed and eaten alive by the macrophages, and the dead bodies are removed from the area in order for healing to take place.

Adaptive Immune Reaction:

Acquisition of adaptive immunity is a learned process. During the first encounter with a pathogen, a signature part of the pathogen - usually, a protein molecule called antigen is recognized by the dendritic cells and the information is passed in succession to lymphocytes of various designations like B-cells, T-cells and ultimately to antibody producing B-lymphocytes. B-cells produce immunoglobulin, specific for that antigen, which when combines with that antigen of the invader, it neutralizes the pathogen. This antigen remains in memory in a subset of B -cells called Memory cells. These lymphocytes live in the regional lymph nodes and the duration of memory is temporary, whereas those B-memory cells move to the bone marrow retain memory permanently.

Like innate immunity, adaptive immunity also consists of a cellular component and a Humoral component.

One can well appreciate there are plenty of opportunities for the invading pathogens to neutralize or evade this body's defense system due to systemic illness or congenital immune deficiencies or use of immune modifying medications or any combination of these. These conditions favor onset of septicemia.

Sepsis:

Sepsis is a severe clinical condition and carries a mortality over 50 %. The inflammatory reactions mentioned in Septicemia are operative here also but in aggressive and unregulated manner in sepsis. During COVID-19 endemic, the high death rate was due to this process and Cytokine Storm term was used to describe this phenomenon. In sepsis, failure of the heart, lungs, kidneys, brain and liver occurs together. A paper published on sepsis based on worldwide case studies, showed Gram negative infection accounted over 50% of sepsis, and gram positive bacteria, fungi and viruses accounted for the rest. The source of infection in order of frequency were the lungs, abdomen, and urinary tract and the underlying conditions that favors sepsis were diabetes mellitus, congestive heart failure, renal failure.

Mechanism.

Most harmful pathogens carry potent endo and exotoxins. These toxins act in many ways to kill or paralyze immune cells and cause tissue injury. Adhesion of endothelial lying cells are weakened and pathogen and toxins gain entry in the organs and continues to damage tissue. White blood cells in their cytoplasm have powerful enzymes in packets called granules and released enzymes are primarily directed towards the pathogens but when produced in excess amount it kills normal cells also and contribution organ damage. In addition, in sepsis major alteration in the concentration of blood coagulation factors takes place due to its effect on liver and local tissue. This causes hemorrhage and also decimated intravascular coagulation and rapid organ failure.

Effect of sepsis.

Vascular wall damage and derailed maintenance of vascular tones and depressed cardiac output produces hypotension and change in consciousness or unconsciousness. Blood flow through the lung capillaries diminishes markedly, producing hypoxia, generation of oxygen radicals and superoxides and more tissue necrosis. Similar changes in the kidneys produce renal failure and electrolyte imbalance.

Role of Macrophages in Sepsis.

Macrophages are of 3 types - resident tissue macrophages (RTMs), monocyte-derived macrophages (MDMs), and transitioning MDMs in the tissue.

Macrophages express a number of proinflammatory chemokines and cytokines, including IL-1β, IL-6, IL-8, CXCL10, and TNFα. And a macrophage subset termed Macro_c2-CCL3L1, which specifically expressed CCL8, CXCL10/11, and IL-6, and a monocyte subset termed Mono-c1-CD14-CCL3, which abundantly expressed IL-1β, CCL20, CXCL2, CXCL3, CCL3, CCL4, and TNF alpha.

Macrophage hyperactivation.

Hyperstimulated macrophages produce Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome. Hemophagocytosis (i.e., engulfment of erythrocytes by activated macrophages), systemic inflammation, fever, cytopenia, hyperferritinemia, and hyperlipidemia, which can be due to inherited defects in cytotoxic T-cell function or triggered secondary to infection or rheumatological disorders.

Role of Platelets in Sepsis. Platelets are tiny lens like discs and platelets have no nucleus but the cytoplasm is packed with powerful chemicals in packet from. Though platelets lack in size but make that up in numbers, around 200,000/microlit of blood. In inflammation and specially in Sepsis, cytokines induce rapid release of platelets from the bone marrow and make individual platelet swell and the surface becomes more sticky and adhere to each other into tiny clots and blocks blood flow in capillaries. This leads to ischemia and tissue necrosis of the kidneys, liver, brain and lungs. Arterial blood fails to load up oxygen and all highly vascular tissues fail to function normally and contribute to necrosis. Released chemicals from platelets recruit further inflammatory cells at the site.

Cytokines in Sepsis.

LTB4. Promotes the release of inflammatory cytokines, recruits neutrophils, increases neutrophil chemotaxis, causes degranulation of neutrophils, increases interaction between neutrophils and endothelial cells, stimulates the release of mediators, enzymes and superoxide, increases ( Interleukin) IL 6, increases pain perception by lowering pain receptors threshold.

ILs are stimulators of inflammation.

These ILs are IL-1, IL-6, IL-12, IL-18 and IL-23

The most pro-inflammatory Cytokines are IL-1 beta and TNF alpha.

Pro-inflammatory ILs activate CD2, CD4, CD8, CD27, CD134 and CD137.

Inhibitors of inflammation ILs are-

IL-10, IL-6, IL-1 beta. They activate CD80, CD152, CD160, and CD223.

Interleukins are secreted primarily by immunocytes. Interleukins (ILs) are hormones like chemicals, function as an inflammatory promoter but also act as anti-inflammatory agents. In the biological system, pro and anti, inflammatory agents are neither good nor bad. Both are required to fight infections, autoimmune diseases and cancers and at the same time must be available for repairs of diseased or damaged tissues. Interleukin 6 (IL-6) is the main Interleukin in the pathogenesis of COID-19 virus inflammatory reactions. 1. IL-6 promotes inflammation. 2. Anti-inflammation. 3. Pathogen clearance. 4. New blood cell formation (hemopoiesis) 5. Reset the metabolic rate of the body. 6. Modification of lipid metabolism. 7. Neural differentiation increased substance-P generation and myelin sheath break-up.

Prostaglandins in Sepsis.

Prostaglandins are produced by a number of cells, some are immunocytes others are not immunocytes. It is derived from Arachidonic acid. PGI2 is a potent vasodilator, and an inhibitor of platelet aggregation, leukocyte adhesion, and prevents smooth vascular muscle proliferation. PGI2 receptors are expressed in the kidney, liver, lung, platelets, heart, and aorta. PGD2 is synthesized in both the central nervous system (CNS) and peripheral tissues. In the brain, PGD2 regulates sleep and pain perception.

Syndrome in Clinical Medicine

Syndrome in Clinical Medicine

P.K.Ghatak,MD

In a NIH publication in 2003, Dr. Franz Calvo et al, defined syndrome as a recognizable complex of symptoms and physical findings for which a direct cause is not necessarily understood. Once the medical science identifies a causative agent or process with a high degree of certainty, physicians may then refer the process as a disease and not a syndrome.

Some well known syndromes now are called diseases and to illustrate - an example is Cushing's disease and Cushing's syndrome. In 1912 Dr. Cushing reported a new disease he call polyglandular syndrome due to malfunction of the Anterior Pituitary gland, He published this entity in 1932 as basophil adenomas of the Pituitary body and named it Pituitary basophilism. Symptoms of the disease - gained excessive weight, mostly around the back of the neck, face and abdomen. Also developed high blood pressure, diabetes, acne and facial hair. In subsequent years the condition was known as Cushing's syndrome. Further studies identified the cause was a tumor of anterior pituitary producing an excess amount of ACTH hormone which in turns putting out excess corticosteroids from the Suprarenal glands. Similar changes were also detected when patients took steroid for a prolong time, as one of the anti-rejection drug following kidney transplants. And also seen in certain cancer of lungs secreting excess amount of polypeptide having similar hormone like actions of the suprarenal gland. Now Cushing's Disease term is reserved for symptom complex arising from tumor of the anterior pituitary and Cushing's syndrome is applied all others causes which can produce some features of Cushing's disease.

If one looks up Syndrome in the Wikipedia, will be surprised to find more than 1600 syndromes. In the index of any textbook of medicine where every entry is listed in alphabetical order, one finds only 3 entries under syndrome, the rest of the syndromes are under the first letter of a name attached to the person discovered the illness. Not all the listed syndromes, however, follows this rule. Some names are retained because the name refers to well understood symptoms by the public, like - Milk - Alkali syndrome and Irritable Bowel Syndrome.

Recent rapid advances in genetics, MRI imaging , sonography, immunology and biochemist solved many obscure causes of syndrome. In the lifetime experience of any well rounded physician might have not see more than 30 syndromes. Certain specialties like Pediatrics are likely see more syndromes.

A few syndrome will be presented here to give a chance to the readers to get an idea about syndrome.

Down syndrome.

Down syndrome arises from abnormalities of chromosome 21. It occurs in 75% cases as inherited and 25% as spontaneous. Each cell of the body contain an additional one full or partial copy of chromosome 21. This generally happen as non-jurisdiction or translocation between chromosome 21 and 14 or 21 and 21 or 21and 22. In 2 to 3 % cases it also occur due to Mosaicism.

Some of the common features of Down syndromes are mental retardation, flat cranium and flat nose bridge, a short neck, large tongue compared with the floor of the mouth, prominent epicanthal fold, structural heart defects, truncal obesity, poor muscle tone an delayed mile stones of development.

Polycystic Ovary Syndrome.

Originally the Polycystic Ovary syndrome was called Stein-Leventhal syndrome because this pair of investigators were the first to report it in 1935. In 1990 NIH added two additional criteria - multifactorial genetic errors and insulin resistance, and finally in 2003 ultsonographic detection of more than 20 cysts in ovary was added and named it Polycystic ovary syndrome. The cause of this syndrome is unknown and symptoms vary widely.

A typical case have these features: Symptoms of irregular and scant menstrual flow or delayed monarchic. Development of acne and facial and body hair of masculine type, obesity, hypertension and insulin resistance and diabetes mellitus. Most cases are due to excessive androgen activities but androgen is normal in minority of cases. In few cases the polycystic ovary syndrome is detected during investigation of failure to conceive. If not treated properly there is high likelihood of development endometrial carcinoma later in life.

Klinefelters syndrome. This congenital condition affects only male child due to having an extra X chromosome. The condition is also known as 47 XXX. The genetic abnormality occur randomly either in the development of ovum or sperm. The condition is generally detected at puberty when the child failed to develop muscle mass and develop feminine body type - gynecomastica, no facial hair and wide hips. They have small genitalia and testicle, scant or absent sperm production and have long legs and short torso. Many have learning difficulties and lags behind reading and writing skill.

Not all affected have all the above features and may pass as normal and only correctly diagnosed much later when one fails to father children. They carry risk of breast and extragonadal germ cell cancers and also osteoporosis.

Turner's syndrome. Turners syndrome is also known as 46 XO. This congenital condition is seen only in female offspring, arises due to missing a whole or part of sex chromosome X; but whether that missing X chromosome is paternal or maternal is not known. The gene responsible for bone growth is SHOX gene and it is missing in Turners syndrome results in the abnormalities of bones in Turners syndrome. At birth the child may appear normal except for a web neck and a broad chest. As the child reaches age 9 or 10 the growth slows down, develop no secondary sexual characters and menstrual cycles. Other features are cubits vulgus, aortic/ pulmonary stenosis and high BP, diabetes mellitus, hypothyroidism and osteoporosis.

Fragil X syndrome: It is a X link cause of mental retardation. Males are more severely affected than females. Incidence is 1:4000 male birth and 1:10,000 in females. Symptoms in female are learning difficulties, variable degrees mental retardation and early onset of menopause. In male the physical characteristics are large ears, prominent jaw bone, high pitched voice, Mitral valve prolapse and increased immobility of joints. This syndrome is associated with autism.

The tip of the long arm of chromosome X carry the mutated Fragil RNA gene results from undue expansion of CCG repeats. More repeats are present more mental retardation is detected.

Marfan syndrome. Marfan syndrome is an autosomal dominant inherited disorder of the connective tissue due to mutations in the Fibrillin gene (FBNA1) on chromosome 15. This results in aberrant TGFB1 and TGFB2 activities. Clinical features of Marfan syndrome are tall structure, long arms and legs, scoliosis, pigeon chest wall deformity(Pectus excavatum), dislocated eye lenses, mitral valve prolapse, aortic root dilatation, aortic incompetence and aortic aneurysm and dissection.

Ehlers-Danlos syndrome. This is another connective tissue autosomal dominant inherited disorder. Mutation of many genes, last count 20 genes, are implicated, and based on severity of symptoms 11 varieties are known. Those who have severe symptoms have mutation of COL5A1 and COL5A2 genes, other mutated genes are TNXB, ADMTS2, PLOD1, FKBP14 and many others. Mutations result is formation of collage tissue in a haphazard fashion and functionally of poor quality specially of the skin, skeletal muscles, arteries, bones and internal organs. Major symptoms include fragile velvety skin, which peals off easily and forms extensive scars. Aneurysm of artery and dissection and rupture of aneurysm and other changes of eyes, heart and bones mentioned under Marfan syndrome.

Irritable bowel syndrome. Irritable bowel syndrome fits the classical definition of the syndrome. A group of symptoms originate in colon and small intestine but cause remains known. Common symptoms are - a sense of not able to evacuate completely after a bowel movement, constipation and low grade abdominal cramps, flatulence and diarrhea, often hard and lumpy stool and diarrhea on the same day, and several bowel movements a day. Various theory are put forward including stress, pressure of modern life, precooked meals, food additive, change of colon bacterial colonies and low tolerance to pain. Both sexes are affected and age of onset - from teens to elderly. It is a common illness.

Milk-Alkali syndrome. It is a self made syndrome due to taking an excessive amount of Calcium supplement to prevent osteoporosis and condition is accelerated and made worse taking mega dose vitamin D3. In previous generation people suffered this complication from taking excessive amount of Tums, Maalox and Mylanta for heart burns and peptic ulcer diseases. Excess alkali present in the form of carbonate in these compounds shifts the blood pH towards the alkaline side. High blood calcium results in excess amount of calcium excreted in the urine. Kidney stones and urinary bladder stones may develop. Renal colic, chronic pain around loin and back are usual symptoms of kidney stone. Left untreated, patients may end in renal failure.

Abdominal Compartment syndrome. This is a serious and often fatal condition arises from several causes but often seen in severe burn victims. Other causes are organ transplants, prolonged abdominal surgery specially repair of abdominal aorta rupture, bullet or knife penetrating injury with severe intra abdominal hemorrhage. Sepsis, abdominal abscess, severe peritonitis and others. Fluids and inflammatory exudates accumulate in and around organs and raises intra abdominal pressure over 20 cm of Hg. This impairs arterial supply and block venous and lymph drainage, producing further damages abdominal organs. Immediate proper fluid management and abdominal surgery in needed to relive the high intra abdominal pressure.

Sudden Infant Death Syndrome (SIDS). A healthy newborn child suddenly stops breathing and dies during sleep. In majority of cases are due to suffocation due to putting children face down in a soft bed for sleep; which favors obstruction of mouth and nose. About 20 % cause remains unknown.

Thoracic outlet syndrome.

 Just below the clavicle at a point it turns towards the shoulder Subclavian artery and subclavian veins and all the nerves arise from the brachial plexus enter the chest wall and course down the medial side of the arm. There is just enough room for the structure to pass. In an abnormal situation like fracture of the clavicle and hematoma formation, a cervical rib and osteoma of the first rib that space becomes too tight for these structures and pressure on artery produce pain in the arm and hand, pressure on the vein swelling of hand and forearm and bluish discoloration of fingers, Pain over the nerve produces tingling numbness of fingers and muscle weakness. The pressure must be relived by surgery to prevent permanent damages to the hand.

Carpal tunnel syndrome.

 This is another syndrome like the thoracic outlet syndrome due to anatomical peculiarity at the flexer surface of the wrist. The median nerve on the way into the palm of the hand has to negotiate through a narrow passage in between wrist bones- Pisform laterally and Hammate and Capitate inferiorly and a strong transverse carpal ligament anterioly. Pain, specially at night , numbness and tingling are the initial symptoms felt in the hand and fingers, at times the pain is felt in the forearm. Later weakness of fingers and thumb, muscle atrophy and ultimately claw hand develops. The causes of Carpal tunnel syndrome are several - Unaccustomed weight bearing repeated flexion and extension of the wrist, pregnancy, fracture of wrist bones and malunion of fractures, synovitis of the flexor tendons, hypothyroidism and myxedema, rheumatoid arthritis, amyloidosis, sarcoidosis, acromegaly and leukemias.

Tarsal tunnel syndrome. Just like carpal tunnel syndrome,Tarsal tunnel syndrome may develop at the ankle joint. Symptoms and causes are practically same except for the site.

Inappropriate ADH secretion. Blood volume and serum osmolarity are maintained by feedback loops on the control center located in the hypothalamus and posterior pituitary gland. In lower blood volume and high sodium content of blood (high osmolarity) no Anti Diuretic Hormone (ADH) should be released from the posterior pituitary. But if ADH is still released in such condition, the situation is called Inappropriate ADH secretion. The causes are many, only important few will be mentioned here.

Syndrome X. Syndrome X is due to abnormal microcirculation of the coronary arteries or coronary vasospasm which results in Angina pectoris.

Syndrome of apparent mineralocorticoid excess, This syndrome is due to 11 beta hydroxysteroid dehydrogenase deficiency inherited on a autosomal recessive mode. Symptoms are early onset of hypertension in childhood, low serum potassium and metabolic alkalosis.

Metabolic syndrome. Metabolic syndrome is a more recent entry in syndrome category; previously the components of this symptoms were known as essential hypertension, hypercholesterolemia, obesity and diabetes mellitus. Under the new name those previous entities are refined and redefined, instead of hypercholesterolemia it is now low HDL cholesterol and high triglyceride. Obesity is now abdominal obesity, Diabetes is replaced by above impaired fasting blood glucose. People Metabolic syndrome are in high risk of developing coronary arterial disease, diabetes mellitus and cerebrovascular accidents.

Stokes - Adam syndrome. This syndrome is a well established a century ago, when physicians used their well cultivated skill of observation and taking pulse over several minutes. Main features of Stokes - Adam syndrome is sudden loss of consciousness and fall to the ground and having epileptic seizures due to complete heart block ( third degree in new definition) and pulse rate of 35 or below. Ventricular fibrillation and ventricular tachycardia also unconsciousness and seizures. At one time it was called Cardiac seizure and that name was better known than Stokes-Adam syndrome.

Long Q-T syndrome. This is an electrocardiogram finding. The time interval between the beginning of q wave and end of T wave on the tracing of an ECG (EKG) is normally 0. 43 millisecond when the heart rate in 72/ minute. In slower heart rate Q-T interval increases in a predictable way. In several cardiac diseases and quinine, procainamid, digitalis, over the counter cold medicines and many other medications can cause undue prolongation of Q-T interval. More longer the interval is there is more chance of Ventricular ectopic beats and precipitation of ventricular tachycardia and ventricular fibrillation. A particular form of multifocal and multi directional ectopic ventricular beats called Torsades des pointes (a French word, meaning twisting around points) is a forerunner of Ventricular fibrillation and death.

Torsades des pointes

Sick sinus syndrome. This is another very significant ECG finding. The natural cardiac pacemaker is the sinus node. In oxygen deprivation from any reason, electrolyte imbalance and certain medications, sinus node fails to generate the electrical pulse wave for heart muscle to contract. This can manifest as slow heart rate over 3 seconds, 1^st, 2^nd and 3^rd degree heart block. These changes are variable and in some cases variable cardic block can be intermittent. The detect the condition a special cardiac monitor is used, which can trace every cardiac beats and record on a preset program. This allows closer examination of any abnormal heart beat and suitable treatment can be offered – often a pacemaker. Main symptom of sick sinus syndrome is missing a heart beat, irregular pulse, palpitation, fluttering sensation in chest, confusion and loss of balance and fall.

Goodpasture syndrome. Goodpasture syndrome is an example how antibody, generated to fight an unidentifiable infection, mistakes its own kidneys as foreign and attacks the collagen tissue  present in the the basement membrane of glomeruli and walls of alvioli of lungs, results in hemorrhage in the kidney and lungs. Main symptoms are bloody urine and coughing out of blood. Other significant symptoms are shortness of breath, chest pain, fatigue , anemia, high BP, fatigue , nausea and vomiting. It is a major illness and requires immediate medical attention.

Alport syndrome. Alport syndrome is multisystem inherited disorder involving collagen IV tissue and results in renal failure, deafness and visual impairment. The defective gene is carried on X chromosome. Male child develops glomerulonephritis at early age and progresses rapidly and unless treated dies by age 40, females are less frequently affected and disease progress slowly.

Nephrotic syndrome. Nephrotic syndrome is a stage in renal failure arises from protein loosing glomerulonephritis. Presence of large amount of proteinin the urine amkes urine foamy, hypoalbumia produces puffy eyes, pale puffy face, ankle edema and scrotal edema. With the further progression of disease ascites and plural effusion are seen. Anemia, fatigue, weight gain from accumulated water develop. Intercurrent infection is common.

Carcinoid syndrome. In a previous blog, carcinoid syndrome was discussed in details. See foot note.

Carcinoid syndrome is due production of a number polypeptides  which have hormone like effects released from one variety of neuroendocrine tumor. Carcinoid tumors are generally arise in the small intestine, stomach, colon, appendix , rectum and liver and pancreas, and also arises in the bronchial tree of the lung. Carcinoid secrete serotonin, histamine, kallikrein, tachykinins and prostaglandin. These are potent vasodilators and produce intense vasodilatation, hypotension, watery diarrhea, asthma like bronchospasm and intense flushing of the face and body. The tumors are small and can be benign or malignant, but pathologically can not be determined whether a tumor is benign or maliganat. In malignant variety the tumor metastasize in the liver.

Dumping syndrome. Dumping syndrome is a number of gastrointestinal symptoms occur when a few minutes after a meal. Vagotomy and reducing stomach capacity by surgery are the principal causes of Dumping syndrome. Following any such stomach surgery, the food leaves the stomach prematurely and enters the duodenum in large amounts overstretching the duodenal wall causing upper abdominal crampy pain, sense of abdominal fullness, nausea, diarrhea, weakness and lightheadedness. And later develops palpitation and rapid heart beats.

Short bowel syndrome. Certain medical illnesses require taking out a part of the small intestine. The small intestine becomes shorter. This changes absorptive capacity of the small intestine and patients develop loss of weight and nutritional deficiency. Crohn disease and ischemic bowel are most common causes.

Zollinger-Ellsion syndrome ( Z-E Syndrome). Z-E syndrome is due to Gastrin producing tumor - Gastrinoma of the duodenum or pancreas. Gastrin stimulates gastric acid production. Majority of Z-E syndrome are spontaneous in origin but 25 % are due to Multiple endocrine neoplasm of type 1( MENS1). Several complication generally develop and are pretty serious – gastric perforation and profuse Gastric bleeding, esophagitis and esophageal atresia.

Budd Chiari syndrome. This syndrome is due to hepatic vein thrombosis which produces liver enlargement, upper abdominal pain, hepatic necrosis followed by cetrilobular fibrosis and jaundice and liver failure. Patients may develop this condition due to hypercoagulable state from inherited conditions like Factor V Leiden, Protein C and S deficiency or from acquired conditions like myeloproliferative disorders or Paroxysmal Nocturnal Hemoglobinuria.

Sjorgen syndrome. This syndrome is named after a Swedish physicians Dr Henrik Sjorgen who reported cases of chronic arthritis associated with dry eyes and dry mouth. It is an autoimmune disease producing chronic lymphocytic inflammation of salivary and lacrymal glands. The microvascular and ductal blockage results from inflammation produce dryness. In addition, exocrine glands of the skin, GI tract, joints, lungs, CNS and kidneys are involved. Arthritis of the hand resemble rheumatoid arthritis. ANA blood test is positive over 1:256 dilution and in addition SS-A, SS-B and RP serology are positive. Sjorgen patients run risk of B-cell lymphoma (non-Hodgkin lymphoma)and antiphospholipid antibody production results in vascular thrombosis.

Gullian Barry syndrome. This is an example of Autoimmune nervous system disease. Antibodies attack myelin sheath of the peripheral nerve and damaged sheath eventually damages the core nerve fibers of axons. Peripheral neuritis causes weakness of muscles of limbs, muscles of respiration and face. What triggers antibody production is not known but a viral infection is likely. From the onset of symptoms of muscle weakness and tingling numbness and pain, the disabilities reaches maximum in 3 weeks and respiratory failure develops.

Pickiwian syndrome. Nearly 200 years ago, Author Charles Dickens in his famous publication “The posthumous papers of the Pickwick club” described obese individual awake but hypoventilate due to reduced sensitivity to hypercapnia of the respiratory center and frequently dowsed off. Pickiwian syndrome is chosen to honor Dickens's astute observation of human nature. People with this syndrome have BMI over 30Kg/square M. Fat accumulates around neck, chest and upper abdomen, have blunt respiration drive even in presence of the strongest stimulus- respiratory acidosis and hypercapnia. Laptin insensitivity explaining the reason for obesity.

Premenstrual syndrome. Million of women suffers irritability, mood changes, weight gain and puffiness of face and hands and feet before the menstrual flow begins. These symptoms are due to hormonal changes necessary to induce shedding of extra growth of endometrium which developed in anticipation of fertilization of a ovum and the beginning of pregnancy.

Congenital Myesthenia syndrome. This syndrome is inherited by autosomal recessive pattern, and also rarely by autosomal dominant mode. Weakness of muscles of the eyelids, eye muscles that moves the eyes, muscles of chewing and swallowing are commonly affected. Repeated movements make weakness worse. Mutation of CHRN gene is responsible for over 50 % of cases, the rest of the cases are due to mutation of RAPSN, CHT, COLQ DBC7 genes. Children fails to suck breast milk. Swallowing and any normal physical activities are affected. Severity of disabilities varies depending upon the mutated genes. All these genes are responsible to provide codes of protein synthesis required for normal functioning of transmission of nerve signal across the neuromuscular junction.

Eaton-Lambert syndrome. Eaton-Lambert syndrome is an autoimmune disease. Immune system produces antibodies which mistakenly attack the Calcium Channels on the nerve endings. This results in fewer functional pathways for nerves to deliver signals to the effector sites involving both somatic and autonomic nervous system. In construst with Myesthenic syndrome, repeated action improves muscle functioning. Small cell carcinoma of the lung is the most commonly responsible for this syndrome, other malignancy also can produce this syndrome. The leg muscles are commonly affected, the effects of autonomic nervous system can be severe in cardiovascular system and urogenital system.

Wernicki - Korsakoff syndrome. This syndrome is a combination of Wernicki encephalopathy and Korsakoff psychosis. Chronic alcohol abuse is the underlying cause of Vitamin B1 deficiency which the cause of this syndrome however, other nutritional deficiency are associated. The symptoms are - inability to develop memory of current events, confabulation and talkativeness, lethargy, confusion and coma. MRI shows atrophy of the thalamus, hippocampus, hypothalamus and enlarged ventricles. The symptoms are reversible if treatment can be started before Wernicki encephalopathy sets in.

Ramsey Hunt syndrome. This is a special case of Shingles. The one side of the face develop palsy of lower motor neuron type and is associated with vesicular rashes on external auditory canal, pinna, mucous membrane of the oropharynx . This is due to reactivation of Vericella - zoster virus (chicken pox virus). The symptoms are pain in the ear, deafness, tinnitus, vertigo, balance and ambulatory difficulties.

Loefflers syndrome. Loefflers syndrome is due to very high eosinophil count in the blood associated with infiltrate of eosinophils in the lung tissue producing pneumonia like symptoms and bronchospasm. In early days it was due to ascaris lumbricoides parasitic infestation when ascaris larvae wondered around to find its fianl residing place in the small intestine. The alergic reaction generated an eosinophilic immune reaction. Now other parasites are known to produce similar reactions during their tissue migration.

Waterhouse- Federick syndrome. Waterhouse-Federick syndrome is a real emergency situation during a miningococcacal meningitis with bilateral adrenal hemorrhage due to toxemia. It produces acute adrenal insufficiency manifested as shock, hypotension, vascular collapse and cerebral, renal and pulmonary inefficiencies. Many other bacterial and viral infection are also known can also produce this syndrome. Immediate intervention to normalize blood volume and tissue oxygenation must be instituted and intravenous corticosteroids admistration is administered along with antibiotics and other therapeutic agents.

Gilbert syndrome. This is an inherited benign liver condition involving high blood unconjugated bilirubin level causing jaundice. Other parameter of liver functions are all normal and no treatment is required.

Osler-Weber- Rendu syndrome. This is also known as Heriditory Hemorrhagic Telangectasia. This inherited in an autosomal dominant mode. It is due to presence of multiple gene mutations. Arteriovenous malformation is present on skin, mainly on the face and mucous membrane of nose, mouth , stomach, GI tract, liver, lungs, spinal cord and brain. Bleeding from involved organs can produce a wide varieties of symptoms, bleeding in the brain can be fatal.

Footnote: For further reading see https://humihealth.blogspot.com/Medical matters.

1. Carcinoid syndrome, - Carcinoid and Neuroendocrine tumors. Blog. Medical matters dated 13 june 2011.  2. Loefflers syndrome. - Round worm Ascaris lumbricoides.Dec 6.2023 3. Korsakoff psychosis. - Speech disorder. Oct,16,202.    4. Sjorgen syndrome. - Collagen & mixed connective Tissue diseases.Dcc14,2022.    5.Zollinger- Ellison synfrome. - Perptic ulcers.Feb 16, 2023   .6.Polycystic Ovary syndrome.Insulin resistanceMarch10,2022.         7. Cushings synrome. Pituitary gland. August 20,2021. + Adrenal gland Oct22,2021.                                             8.Rumsey Hunt syndrome. Chicken pox Feb16,2023,    9.Myesthenic syndrome.Neuromusculat transmission, Dec22,2022.   10. Milk- Alkali syndrome. Kidney stones April16,2022.

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Cyst

 

Cyst:

P.K. Ghatak, MD

What is a Cyst:

A cyst is a closed sac found anywhere in the body that may contain fluid or any other material - pus, blood, air/gas or other substances. A cyst has a complete wall, and the wall may be composed of one or more layers. The fluid filled cysts, in general, have an epithelial lying. Cyst, unable to drain its content because it had no duct.

Types of Cysts:

1. Congenital. 2. Infective. 3. Retention. 4. Malignant.

Congenital Cysts: Examples are Renal, Hepatic, Intestinal cysts,

How congenital cysts develop. - Those organs, like liver and kidneys, have two sources of origin during the embryonic stage. At the end, two developed structures are jointed together and the partition wall is absorbed, making it a functional organ. When one or more points of union between them fails to disappear, fluid accumulate. In case of liver bile accumulate and urine in case of simple renal cysts.

Infective Cysts: Example - Lung abscess.

Any infectious or Inflammatory process begins with accumulation of WBCs, macrophages and platelets at the site of infection. To limit the spread of infection, the cellar layer acts as a barrier. This cell wall is gradually replaced by a fibrous wall. The enzymes released from the inflammatory cells dissolve the cells into a paste called as Pus. This pus filled cystic structure is known as an abscess.

Retention Cysts: Example – Salivary cysts.

Inside the mouth, salivary glands of various sizes are present. One of the salivary gland duct may be injured by dentures, fish bone or chicken bone. An inflammation begins and the wound heals by fibrosis. Fibrosis may completely block the duct and saliva accumulates results in a cyst formation

Malignant Cysts: Example – Cystadenoma of the nasal sinuses and lungs.

One of the mucous gland of the sinus or lung may turn into a cancer. Some cancers retain glandular structure called cystadenoma, other cancerous glands turns anaplastic cancer.

Special cysts:

A few are discussed here.

1. Sebaceous cysts.

Sebaceous cysts arise at the dermatomal junction due to accidental invagination of sebum secreting cells under the surface skin layer. The common sites are temple, head and back.

These cysts are slow growing and painless. The wall is thick and fibrous and as a cyst grow it raises the overlying skin. The cyst contains sebum. It looks like soft cheese and has an offensive odor. The cyst is attached by a long stock to the deeper later of the dermatome or to the suture lines of craniofacial bones.

Dermatomes junction where sebaceous cysts are seen

2. Hemorrhagic cyst of the liver.

There are several reasons for the development of hemorrhage inside a hepatic cyst. Some hepatic cysts are estrogen dependent and bleeds when women are on birth control pills. There is sudden increase in the size of the cyst and the tense cyst wall causes sudden upper abdominal pain. When a cyst ruptures, the pain intensify and felt over a wider area of the abdomen. Bleeding may not be controlled by itself and patients may go into shock. Immediate surgical intervention may be necessary.

3. Polycystic disease of the kidney.

This is an autosomal dominant mode of transmitted inherited disease. Patients are generally middle aged individual, presents with severe hypertension which is not controlled by medications. Kidney transplant is necessary to control BP. Ultrasound study of the abdomen is diagnostic and for confirmation CT angiogram is generally performed. Polycystic liver is often associated with this condition.

4. Cysts of the peritoneal cavity. Several types of Cysts present in the peritoneal cavity. A cyst may originate from the mesentery, peritoneum or GI tract. Besides sonography, other images are necessary, including MRI to diagnose cysts of peritoneum. Based of locularity, wall thickness, partition walls, consistency of content and presence of calcification may narrow preoperative diagnosis. But at laparotomy a definitive diagnosis often made – such a cyst may be serous, chylolymphatic, or lymphangioma.

5. Polycystic disease of ovary.

If an ovary contains more than 20 cysts (follicles), it is termed polycystic ovary; if in addition, the woman has hirsutism and insulin resistance, an excess of androgen hormone activities and disruption of the anterior pituitary negative feedback loop then the condition is called Polycystic Ovary syndrome. It is an autosomal dominant inherited disease. Patients have scant menstruation, infertility, facial and body hair of male pattern, diabetes mellitus2, hypertension, obesity and more incidence of cardiovascular disease. If not properly treated, generally develop endometrial carcinoma.

6. Chocolate cysts of Ovary.

In endometriosis, the endometrial tissue may be deposited on the ovaries. The autoimplant tissues grow into cysts and bleed inside coincide with menstruation. These cysts are dark and are relatively large.

7. Hydratic cysts. Echinococcous is the tape worm infects dogs, seeps and nearly all wild carnivorous mammals. In the dog's feces, infective cysts are present. When dog's feces contaminate food and drinks and humans sallow these infected cysts, the larvae emergein the stomach and spread out in various organs. Because humans are not a definitive host, these larvae can not develop further and become cysts but continue to grow and produce daughter cysts and become multilocular cysts. The burden of the parasitic cysts are borne by the liver, lungs, muscles and brain. As these cysts grow, they produce obstruction of flow of bile in case of the liver and produces obstructive jaundice. In the brain, obstruct CSF (cerebrospinal fluid) circulation results in Hydrocephalus. Increased intracranial pressure becomes a serous medical problem. To cure, one or other surgical produces are required.

8. Cysticercossis. Tenea solium is a tape worm and it infects pigs. Infected animal muscles and tissue contains many infective cysts. When uncooked or lightly cooked meat humans ingest, these cysts hatch into larvae and the larvae are carried by blood to the liver, brain and other tissue. In these organs, the larva develops into cysts. Like hydratic cysts cysts are multilocular and increases intracranial pressure. Usually, in untreated cases, the wall of the cysts are calcified.

9. Amoebic cystic abscess of liver and lungs. In tropical countries, humans are frequently infected by Entamoeba histolytica. Amoebic dysentery is the usual manifestation and amoeba burrows in the wall of the colon, producing colon ulcers and colitis. Occasionally amoeba are carried by blood to the liver and and a liver abscess is formed. Adhesion develops between the upper surface of the right lobe of the liver and the right dome of the diaphragm. Amoeba enters the plural cavity and produces empyema and also lung abscess.

10. Hydrocele. The covering of testicle, which maintains fluid content. When fluid balance is disrupted and excess fluid accumulate in the testicular sac, it called hydrocele. Surgery is required to cure.

11. Meningocele. Meningocele is a neural tube defect develops during early embryonic stage. Various degree of severity, from simple meningocele with cerebrospinal fluid cysts associated with no neurological symptoms to herniation of the brain tissue with neurological complication, are seen. Treatment is surgical.

12. Myelomeningocele. Spinal neural arch fails to close completely and the condition is called spina bifeda.It is often associated with herniation of spinal nerve tissues and CSF. The condition is called Myelomeningocele. Various degrees of neurologic defects and the urinary symptoms are usual. Treatment is surgical but significant debilities remains after a successful surgery.

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Ophthalmic Migraine

Ophthalmic Migraine.

P.K.Ghatak, MD.

People in general understand Migraine, however Ophthalmic Migraine may not be that familiar to the public. The medical term of this entity is Retinal Migraine. Retinal migraine points to an abnormal condition of retina producing of migraine, whereas a migraine with Ophthalmic aura consists of eye symptoms which are due to abnormal blood flow in one or other areas of the brain.

What are the symptoms of Retinal Migraine / Ophthalmic migraine:

Patients experience sudden onset of blurred central vision of one eye, as if some smug is on the eyeglasses or a film of mucus in one eye. As he/ she tries to get ride it, the blurred area enlarges and lines line appear with zigzag shapes. A bright cured line or comma shaped figure appears which simmers and the line has sharp edges like a shattered glass.

The shimmering light does not disappear after closing eyes. These symptoms last a few minutes to 15 minutes, and then the normal vision slowly reappears and the shimmering line disappears. Some patients also experience dull pain behind the effected eye.

Symptoms are recurrent and limited to one particular eye. Rarely, some patients have both eyes effected but always one eye at a time.

The gray area is the bind spot and the wavy zigzag line is shimmering light.

Are there other causes of blurred vision and shimmering of bright light.

The following conditions also produce some of these symptoms and generally last longer or permanently. The onset and progression of symptoms vary from one condition to the other.

1. Retinal tear

2. Central retinal artery insufficiency or blockage.

3. Central retinal vein thrombosis.

4. Stroke and transient ischemic attacks.

5. Migraine with visual aura, read a previous blog: Migraine - A Miserable Human Malady . date-May27,2019

6. Macular degeneration

7. Giant cell arteritis.

What causes Ophthalmic Migraine:

No identifiable cause is known. Various health conditions and several personal habits are linked to Ophthalmic migraine. Only genetic predisposition is perhaps acceptable.

It is also possible that irritation of some fibers of the Ophthalmic division of the trigeminal nerve triggers spasm of retinal arteries and initiate an attack of migraine.

Treatment:

Ophthalmic migraine is self limited and usually benign. It is very important, however, to see an eye specialist to confirm that the visual symptoms are due to Ophthalmic migraine and not due to more serious conditions listed above.

General advice for prevention or shorten the duration of Ophthalmic migraine.

Limit time spend looking at the computer/ cellphone light. Limit exposure to cigarette smoke and any irritant spray or perfume. Control Blood pressure, blood sugar and cholesterol. Check vision and use eyeglasses if required.

Kennedey's Disease and Other Motor Neuron Diseases.

 

 Kennedy's Disease and other Motor Neuron Diseases.

             P.K. Ghatak, M.D.

In 1966 Dr. William R. Kennedy reported a case from Minnesota of an 54 old man with progressive weakness of limb muscles and facial muscles. Working an an assumption that it was an inherited disease, he studied all the members of the entire family for evidence of similar cases. He concluded that it was inherited as X-linked disease, a new type of spinal bulbar muscular atrophy. Subsequently, other investigators found abnormal sex hormone levels, gynecomastia, low sperm count, testicular atrophy, diabetes mellitus and some sensory impairments in these patients. This disease in known as Kennedy's disease.

Motor neuron disease(MND).

In 1933 Russell Brain of UK coined the term motor neuron disease to a group of neurodegenerative disease. Until then, these diseases were known by their neuroanatomical pathophysiological basis. MND is the third most common degenerative disease of the nervous system, after Alzheimer disease and Parkinson's disease.

The incidence of MND is 2 to 3 per 100,000 per year in the USA; 0.8 in the Far East, 1 to 2 in South Asia and 3 to 4 in Europe per 100,000 respectively.

Motor Neuron Disease (MND) includes - Amyotrophic Lateral Sclerosis, Progressive Bulbar Palsy, Primary Lateral Sclerosis, Spinal Muscular Atrophy, Post-polio Syndrome and Kennedy's Disease. However, many others consider all MNDs are variation of ALS ; still others include Pseudobulbar palsy, Facial Skeletal Atrophy, Spinobulbar Atrophy and Hereditary Spastic Paralysis as distinct additional entities of MND.

The motor neuron cells of the cerebral cortex are called Upper motor Neurons (UMN). These cells make synaptic connections with motor neurons of the cranial nerves and the anterior horn cells of the spinal cord. UMNs do not directly carry impulses to muscles fibers. The motor neurons of the cranial nerves and the anterior horn cells of the spinal cord are celled Lower Motor Neurons (LMN). They are the final common path of all motor actions – voluntary actions and involuntary reflex actions.

The common characteristic of Motor neuron disease is the progressive loss of either UMN or LMN or both UMN and LMN. The motor cranial nerves are 3^rd,4^th, 6^th, 9^th, 11^th and 12^th. The following cranial nerves are mainly sensory but also carry motor fibers – 5^th, 7^th and 10^th.

Amyotrophic Lateral Sclerosis (ALS).

In ALS, both UMN and LMN are affected. In the USA, ALS is better known by Lou Gehrig's disease, named after a famous baseball player who developed ASL in 1939. The disease usually manifests in the midlife as muscular twitching and stiffness, then progressively develop muscle weakness of limbs, larynx, throat and the rest of the body. There are wide variations of the site of origin of weakness, spread and rate of progression of the disease. In some cases muscle weakness starts and stays limited to limbs and in others in muscles of swallowing and breathing. However, in the most cases ALS involve both groups of muscles and the disease progress rapidly. The death is usually in 3 to 4 years from respiratory failure. [ amyotrophy = artophy ]

Progressive Bulbar Palsy.

The muscles supplied by motor neurons of cranial nerves slowly degenerate, it is a LMN disease. Health and survival of these muscles are vital for for longevity, once symptoms related to muscle weakness begin the prognosis becomes poor. In some patients, a full picture of ALS develop.

Primary Lateral Sclerosis (PLS).

In PLS, only UMNs are involved. The symptoms of PLS starts between 40 and 60 years of age. The initial symptoms are muscle stiffness and unsteady balance. Weakness of skeletal muscles develop, but life is not cut short in many PLS patients, while others are not.

Spinal Muscular Atrophy (SMA).

The incidence of SMA is less than ALS. It mainly affects the LMN. Limb and facial muscles become weak and atrophic, spinal curvature develop. Four different types of SMA are known,

Type 1 also known as Werdnig- Hoffman disease. The disease begins at 6 months of age, muscle tone is poor and reflexes are slow and feeble. Milestone of development lags behind. Ultimately, the child develops difficulty in breathing and death is from respiratory failure.

Type 2. It is a milder form of SMA. The symptoms stats at 6 to 12 months of age. The child shows difficulty is standing by himself and walking. But does not develop respiratory muscle weakness.

Type 3. It is also called Kugelburg-Welander disease. The symptoms start between 3 and 10 years of age, mainly in the form of joint and spinal column deformities due to short muscles and tendons.

Type 4. The symptoms appear at around age of 30 year. The muscles of the arms and legs are weak and later become atrophic.

Post-polio syndrome.

Poliomyelitis virus affects the anterior horn cells of the spinal cord. Those cells survive the initial onslaught and recover, however, are susceptible to viral infection and affected in a variety of illnesses including surgery and general anesthesia. The most offending organism is is E-B virus. Patients develop flaccid paralysis of limbs or difficulty in swallowing, nasal intonation of speech and breathing difficulties. Recovery is the general rule with gamma globulin therapy and other measures to preserve and recover muscle functions.

Cause of MND.

Most cases occur sporadically and not inherited. Only about 5 to 10 % of cases are due to inherited mutations of a gene or multiple genes. As of today, many genetic mutations are mentioned but here only those mutations are proven to be the cause, will be presented.

Kennedey's Disease.

The proximal arm of the chromosome X carry DXYS gene which encode CAG (cytosine, Adenine and Guanine) nucleotides. Mutation of DXYS gene results in an expansion of repeat of CAG from the normal 30, to 40 - 60 times. Over crowding, results from so many repeats, interfere with functioning of the gene that encodes proteins for androgen receptors. Deficiency of androgen hormone results in testicular atrophy, oligospermia and hypogonadism. 

ALS.

In ALS, mutation is present in the SOD1(superoxide dismutase 1) gene and to a lesser extent in the SOD2 gene. Mutation of these two genes result in accumulation of superoxide dismutage and other radical. Accumulated radical sicken and kill neurons. The chromosome 9 open reading frame 72 (C9orf72) encodes a protein that ferries nerve impulses across the synapses and to the muscle end plates. When muscles lose nerve connection, they undergo atrophy and degeneration. The speed of progression of ALS depends on the degree of mutation of these genes and responsible for the wide variation of the clinical features of ALS.

The mode of inheritance is usually autosomal recessive, but autosomal dominant and X-link recessive modes are also seen.

Spinal Muscular Atrophy (SMA).

 Motor neurons require a special protein, Survival Motor Neuron (SMN) protein. The SMA1 gene encode SMA protein and SMA2 gene also encodes SMA protein to a much lesser extent. SMA1 gene mutation vary greatly and some patients carry multiple copes of mutated gene. The more mutated genes one carry, the disease manifest early and clinical picture gets worse. A normal SMA 2 gene can have beneficial influence but if also mutated then outlook becomes dismal. The clinical types of SMA are due to this variation of the number of mutated SMA1 and SMA2 genes and their ratio.

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Jaundice

 

Jaundice

P.K.Ghatak, MD

Jaundice is a yellowish discoloration of the body, easily noticeable in the white of the eyes, under the surface of the tongue and skin. It is a symptom and not a disease. It is the job of a physician to find the case of jaundice.

The immediate cause of jaundice is presence of excess amount of a pigment - Bilirubin in the blood. Bilirubin is a waste product, appear in the blood from breakdown of the hemoglobin. A small amount of bilirubin is also obtained from muscles and liver and from enzyme system containing iron molecule as in Cytochrome. Bilirubin gives straw color to the urine and yellow-brawn color to stool. A normal bilirubin level in the serum is less than 1 mg/dL, and when jaundice is detected the bilirubin level reaches 2.5 mg/dL or higher.

The liver cells filter bilirubin out of the blood and excrete bilirubin in the bile. Bile reaches the small intestine intermittently from the gallbladder. The bilirubin is partly absorbed from the intestine and returned to the blood. In the kidneys the bilirubin is filtered out and excreted in the urine, the part not absorbed in the gut, is eliminated in the stool.

The possible ways excess bilirubin can accumulate in blood when an excess of Red Blood Cells are destroyed, in diseases of the liver cells, obstruction of the common bile duct and gallbladder diseases.

Physiological Jaundice in all Newborn.

A fetus draws oxygen and nutrients from mother's blood through the placenta. The oxygen level of the placental blood is lower than the oxygen in the lungs. To circumvent this problem, the fetus is provided with a special hemoglobin - Fetal hemoglobin, which is capable of drawing adequate amount of oxygen in low oxygen environment. The fetal hemoglobin is not needed as soon as the child is born and takes the first breath in the form of a cry. This acts fills up child's lungs with air. A mechanism is in place in switching production of adult type of hemoglobin and stop fetal hemoglobin production. The fetal hemoglobin of the newborn begins to breakdown. As a result, the bilirubin in the blood of the newborns are higher than adults. The normal range of bilirubin in the newborn is about 10 mg/dL on the 1^st day and 15.18 and 20 mg on successive 2nd,3rd and 4^th day. Then the bilirubin level declines rapidly.

Congenital enzyme deficiency diseases, namely Gilbert syndrome and Dubin- Johnson syndrome. Both are inherited as autosomal recessive pattern. Both are benign causes of jaundice, and produce no ill effects. In Gilbert syndrome, Gluconosyltrasferase enzyme is deficient due to mutation of UGT1A1 gene. In Dubin-Johnson dyndrome a transport protein is deficient which produces accumulation of bilirubin in blood and in the liver.

Bilirubin in then blood.

In normal adults, the bilirubin is present in two forms - conjugated bilirubin and unconjugated bilirubin.

The conjugated bilirubin is formed by the liver cells by reacting it with Glucoronic acid. In the laboratory, it is detected by a test called Direct Acting Bilirubin. The most of the bilirubin in the blood under normal condition is conjugated direct acting bilirubin. A small amount of bilirubin in the blood is unconjugated and is detected in the lab by adding alcohol, and the test for this reason is called indirect acting bilirubin.

Breakdown of hemoglobin produces bilirubin but not in every instance jaundice happens – development of jaundice depends on degree and duration of hemolysis and functional status of the liver and Kidneys.

Cause of jaundice:

A. RBC destruction.

1. Congenital causes

a. abnormal shape and size of RBC.

RBCs travel through capillaries, the diameter of the capillaries are just large enough for RBCs to pass through. In congenital abnormal sized RBC, Hereditary Spherocytosis and Hereditary Elliptocytes, in attempting to negotiate through the narrow capillaries, the RBC membrane breaks down, releasing hemoglobin.

b. Congenital absence of RBC enzymes. In G6PD (glucose 6 phosphate deficiency) and Pyruvate kinase deficiency, the RBCs are fragile and breaks down easily. In G6PD deficiency the cell membrane fails to maintain integrity and spleen breaks down damaged RBC, in Pyruvate-kinase deficiency, ATP level falls leading to dehydration of RBC and deformed RBCs are similarly broken down.

c.  Abnormal hemoglobin. In Sickle Cell Anemia, the sickle shaped RBCs unable to negotiate through capillaries and breaks down. Similarly, in beta Thalassemia the RBCs break down.

2. Other causes of Intravascular hemolysis and its mechanism.

1	ABO blood group mismatch	Presence of antibodies in recipient attacking donor RBCs, on repeated transfusion development of antibodies attacking recipient's own RBCS
2	Mycoplasma infection and cold agglutinins	i-antigen initiates antibody production, which mistakenly attack RBCs, reaction takes place in cold. HIV, E-B virus and other virus also produce cold agglutinins and complement is required for hemolysis.
3	Streptococcus infection	Hemolysin is generated by growing streptococcus in the infected tissue, produces 3 types of hemolysis -alpha, beta and gamma
4	Staphylococcus infection	Alpha, beta, gamma, delta, omega hemolysis generated by staph colonies. In addition, PLV toxin drill holes in the RBC membrane and hemoglobin leaks out in the serum.
5	Enterococcus	Most virulent of all coccal infections, generates alpha and beta hemolysins.
6	Clostridia perfringens	Produces gas gangrene. It produces Alpha toxin which liquefies RBCs, muscles and soft tissues.
7	Autoimmune hemolytic anemia	Misdirected antibodies causes hemolysis, generally follows drug therapy. The common drugs are Cephalosporins, Penicillin, Levodopa, Levofloxacin, Nitrofurantoine, NASDs, Dapsone, Methyldopa, Quinidine and Pyridium.
8	Warm agglutinins	warm antibodies are present in congenital syphilis, SLE and Scleroderma and bacterial infections
9	Malaria and Babesosis	Different morphological shapes and sizes of the stages of developing young forms and parasite load rupture RBC membrane.
10	Complications of pregnancy	Toxemia of pregnancy called Eclampsia and HELP syndrome
11	Non-immune hemolytic anemia	In paroxysmal cold agglutinins hemolysis, antibodies develop following viral or bacterial infection and unknown causes, hemolysis takes place at body temperature. Paroxysmal Nocturnal Hemoglobinemia develop due to an acquired mutation of PIGA gene, the main features and hemolysis, thrombosis and smooth muscle dystonia. Death occurs from the bone marrow failure,
12	Poison and Toxins	RBCs are destroyed by enzymatic action of snake poison and similarly by poison of other animals and plants.
13	Artificial mechanical heart valves and other medical devices	The plastic or metal surface of these devices, including the heart-lung machine, are noncompliant and as RBCs are thrown against them, The RBCs rupture.
14	Other illnesses including hematological and solid organ malignancies.	Some hematological conditions produce abnormal shape and sizes of RBCs, others produces hemolytic cytokines, still other changes coagulation factors and platelet function which causes capillary thrombosis, intramuscular hemolysis.
16	Cirrhosis of liver	Usually chronic addiction to alcohol and also in non-alcoholic steatosis.

3. Obstructive Jaundice.

Obstruction of free flow of bile from the liver to the duodenum can happen in various medical conditions, the chief among them are Gall stones, Cholangiohepatitis, Liver flukes in East Asia countries. Cancer of the head of the pancreas, Metastatic cancer of lymph nodes of portahepatis and lymphoma, and Hepatocellular carcinoma

The main features of obstructive jaundice are progressive deepening of jaundice. Dark urine and light color stool. Intense skin itching due to deposition of bile salt in the skin. Enlarged liver.

4. Viral Hepatitis.

Virus infection disrupts cellular function of the liver cells and bilirubin is not extracted, also inflammatory edema of the liver blocks narrow intra lobular bile canniculi, preventing the forward flow of bile through the duct system

Many viruses infect the liver. The virus that cause the most serious form of hepatitis is Hepatitis B, followed by Hepatitis D and Hepatitis C. Hepatitis A virus and Hepatitis E virus infections break out in South Asian countries following monsoon rain and floods, contaminating drinking water sources with human feces. The hepatitis produced by these two viruses are generally milder and self limited. To name few other important hepatitis viruses are Yellow Fever virus, Adenovirus – Lassa fever is a serious infection. Filovirus – Ebola and Marburg fever viruses. Herpes virus- Cytomegalovirus infection, Epstein-Barr virus and Human Herpes virus 6 are important in this group.

In day to day practice, jaundice is not a rare finding. Off the causes mentioned above, these medical conditions are likely to be encountered.

1. Viral hepatitis. 2. Acute and chronic cholecystitis and gall stone obstruction of bile duct. 3. Bacterial infections. 4.  Cirrhosis of the liver 5. Sickle cell anemia and Thalassemia. 6. Mismatched blood transfusion. 7. Cancer of the head of pancreas and Hepatocellular carcinoma of the liver. 8. Lymphoma. 9. Therapeutic use of certain drugs. 10.Cholangiohepatitis. 11. Liver fluke infestation of biliary system in certain South Asian countries. 12. Gilbert syndrome and Dubin-Johnson syndrome.

 An attempt is made to point out jaundice develops not only from hepatitis but a host of other medical conditions. The obstructive jaundice requires urgent surgical consultation. To relieve intense itching and painful enlarged liver, a transcutaneous bile duct stent can be placed to drain the bile in the small intestine, bypassing the obstruction.

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