IgA and IgA associated diseases

 

                               Immunoglobulin A (IgA) and disease associated with IgA

                                               PKGhatak, MD

Immunoglobulin A is the dominant Immunoglobulin secreted by the submucosal lymphoid tissues of the gastrointestinal tract, salivary glands, ducts of secretory glands, respiratory and genitourinary tracts; in addition, IgA is also present in tear and breast milk. The combined mucosal lymphoid tissue is the largest lymphatic system and much more than the combined lymphoid tissues of the spleen, lymph nodes and liver.

IgA plays a prominent role in keeping infectious agents from entering or invading the body through these tracts.

IgA is present in two subtypes. IgA1 or serum IgA and IgA2 or secretory IgA. The secretory IgA is 2/3 of the total IgA.

The amount of IgA secreted in a day is much greater than IgM and IgG combined. It is estimated that 5 Gm of IgA is produced daily.

Regulation of IgA production.

Polysaccharide moiety of a compound antigenic for IgA, instead of a protein that acts as the antigen for other immunoglobulin synthesis. The antigen is recognized by the dendritic cells and T-cells are located in the lymphoid tissue of the submucous layer of different tracts, and subsequent communication with B cells, memory cells, and plasma cells work in the same way as the antibody production of other sites.

During fetal development T cells migrate from the thymus to GI, Respiratory, GU tracts, breast tissue and other sites.

The initial production of secretory IgA by the mucosal B-cells is a polymer IgA (pIgA). A specific pIgA receptor (sIgA R) binds with pIgA and carries pIgA molecules across the epithelial cells into the lumen. In the lumen, pIgA is broken down as a secretory IgA (sIgA) monomer. sIgA binds with the mucous layer of epithelium and prevents the attachment of invading pathogens to the surface epithelium. The secretary IgA acts also as an anti-inflammatory agent. But the secretory IgA does not bind with complement, so the pathogenic organisms are not phagocytized by the macrophages but eliminated by peristalsis. Epithelial membrane continuity is essential for mucosal defense. If the mucous layer is disrupted, as happens in Ulcerative colitis and Crohn's disease, the bacterial invasion of tissue must be met with other standard methods of immunity and inflammation.

The differentiation of T cells to secretory immunocytes and memory cells is due to the action of cytokines; of the cytokines, the T-cells derived growth factor (TDGF) and IL5 are important.  The serum IgA is produced in the bone marrow, spleen and lymph nodes.  The liver is the main source of the breakdown of IgA.

Pathogens that evade secretory IgA:

Neisseria gonorrhoeae, Streptococcus pneumoniae, Hemophilus influenza type B, and certain spores of the fungus are capable of destroying secretory IgA. The drug Vancomycin can also degrade secretory IgA.

Congenital deficiency of IgA:

Some patients may have no or very low IgA from birth, in others, a low IgA is due to the presence of autoantibodies. If such an individual is transfused with blood or plasma products, severe allergic and anaphylactic reactions may occur due to the presence of IgA in the transfused products. There is a high association between autoimmune diseases with IgA deficiency.

IgA associated diseases:

IgA Nephropathy (IgA N).  It used to be known as Berger's disease.

IgA Nephropathy is the most common type of Nephropathy in Asia and also in the world.

It is postulated that the respiratory tract bacteria produce Deglutamylation of IgA molecule. This degalactosyzed IgA (dIgA) becomes an antigen and antibodies are produced. Then antibodies and dIgA combine and this Antigen + Antibody complex is deposited in the extracellular matrix of the Glomeruli of the kidney leading to IgA Nephropathy. The previously held theory was that aberrant glycosylation of IgA leads to polymerization of IgA and because of the complex's large size, these complexes are deposited in the mesangium of glomeruli. Inflammation starts as a result, and glomerulonephritis progresses to membranous glomerulonephritis with crescent formation.

IgA N may run in families, but the abnormal gene/genes are not identified, and the mode of inheritance is unknown.

Clinically two groups are identified.

Benign and Aggressive types.

Benign IgA N:

Gross hematuria develops in a day or two following a URI (upper respiratory infection). Hematuria stops after a few days but may persist for a period as microscopic hematuria. Some of these patients go on to develop proteinuria. Over a period of 10 to 20 years, the protein loss in the urine becomes very significant, and they develop edema of the hands, feet and face. Renal functions gradually deteriorate and eventually end in chronic renal failure.

Aggressive IgA N.

At the onset, the symptom is gross hematuria following a URI but soon or simultaneously developing Henoch Schoenlein purpura, Dermatitis herpetiformis, Bulbous epidermolysis bullosa, vasculitis of skin, liver and heart.

The deterioration of renal function is rapid and if treatment is delayed, then renal failure develops.

Diagnosis:

IgA levels are higher than normal, but the disease activities do not correlate with blood levels of IgA. A kidney biopsy is required for diagnosis. Immune-florescence staining shows deposition of IgA and complement C in the glomerular mesangium.

Henoch Schönlein purpura.

Purpuric eruptions develop following a URI. The purpura is mostly seen in the legs, buttocks and sometimes in the hands, face and trunk. The purpura is more abundant along with the pressure points like the sock line and the waistband. Purpura is palpable and does not fade away upon applying pressure. Children between 2 and 6 are mostly affected. Male children and white and Asian children are more vulnerable to HS purpura. The underlying pathology is a vasculitis of small vessels of the skin, mucous membrane and joints. Lesions in the mouth and arthritis may develop. GI symptoms are common and some also develop IgA nephropathy.

Skin lesions.

Dermatitis herpetiformis.

Clusters of raised red, intensely itchy lesions develop on elbows, knees, buttocks, occasionally on arms and on the scalp. The lesions are intensely itchy. Often blisters develop and scars form when opened up from scratches.

People of the age group 30 to 40 of European heritage develop recurrent lesions. Oral and GI lesions also occur. Aphthous ulcers in the mouth, inner side of cheeks, gum, tongue and palate. Pits and fissures on the enamel of teeth may appear. The GI manifestations are bloating, cramps and diarrhea.

Cause.

IgA antibodies develop against the skin epidermal transglutaminase. It is the skin manifestation of Gluten enteropathy from gluten sensitivity.

Diagnosis.

Demonstration of IgA deposition in the upper layers of the dermis by immunofluorescence.

Dysmorphic Epidermolysis Bullosa.

IgA deposition at the junction of the basal layer of the epidermis and papillary cells of dermal held by collagen fibrils are damaged by the process. The epidermis is easily lifted off from the dermis with minor trauma. Blister formation and secondary infections are common. Epidermolysis Bullosa is an inherited disease. It is inherited by autosomal recessive and autosomal dominant modes, and multiple gene mutations are present.

There are several clinical types based on clinical presentation and the associated involvement of other systems. GI, GU, Respiratory, and ENT may variously be involved.  It may be present at birth or at any time later in life. It is a serious disease. There are serious complications if patients initially respond to treatment. Esophageal stricture and cancer are usual.  Diagnosis is made by immunofluorescence staining of the biopsy tissues. The prognosis is variable but not good in general.

IgA is the principal immunoglobulin in keeping the GI tract and other mucous membranes of hollow organs free of pathogens. Because of constant contact with bacteria, some of the bacterial degradation products/secretory enzymes become antigenic and antibodies are produced. Antibodies can react with normal tissues like nerve cells, GI cells, etc. This hypothesis has generated a new look into the pathogenesis of Multiple sclerosis, Parkinson's disease, etc. In the future, more and more laboratory confirmations will be available

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Hemoglobin and Beta Thalassemia Trait

 

                                        Hemoglobin and Beta Thalassemia Trait

                                                PKGhatak, MD

Hemoglobin is a metalloprotein. Four molecules of Ferrous iron are attached to four individual porphyrin rings known as protoporphyrin in a tetrahedron configuration. This compound is called Heme. The porphyrin rings are interlinked and attached to the Polypeptide chains (protein) called Globins. Of the total four globins,  two identical globins are Alpha globins and the other two are Beta globins. The alpha and beta globins differ from each other by the numbers and sequence of amino acids composition.

In the developing human fetus, globin chains are different. Two alpha globins are the same but the beta globins are replaced by Gamma globulins and the hemoglobin is called fetal hemoglobin or hemoglobin F. In a newborn, the fetal hemoglobin is rapidly replaced by adult hemoglobin (A).

The variations in globin amino acids sequence, substitution or deletion produce many abnormal hemoglobins, most of them are not important for humans but a significant one is hemoglobin S of Sickle cell disease and the other is the hemoglobin of Thalassemia.

The genes responsible for coding goblin chains are inherited by the recessive mode. When both parents are carriers of abnormal globin genes, the progeny will be homozygous and the resultant disease is called Thalassemia. If one parent is the carrier then out of four pregnancies, two children will be carriers and the condition is known as the Thalassemia trait.

The defective coding gene of the Beta globin results in deficiency of the beta chain synthesis, it is located on chromosome #11p15.5 location. Due to the deficiency of the beta chain, the metalloporphyrin joins with two globin chains called the Delta chain. In normal circumstances, the delta chain is present in a minuscule amount. But in Beta Thalassemia trait the delta chain becomes significant. The resultant hemoglobin (designated alfa2 delta2) or A2. The A2 hemoglobin does not function like normal hemoglobin. The red cells (RBC) containing A2 hemoglobin have a shorter life span and are broken down by the spleen. The blood count of Beta Thalassemia trait patients shows a picture almost like iron deficiency anemia. The red cells are smaller, a bit paler in color and some of the RBC show bluish spots called basophilic stippling and the presence of target cells and occasional nucleated RBC. The total number of red cells is either normal or higher, the MCV is high normal or just above normal, the reticulocyte count is high. The serum iron, ferritin and ferritin saturation are high normal, or just above normal levels. The rest of the hemogram appears like iron deficiency anemia. Another major difference in beta thalassemia is the red cell mean width distribution called RWD. The RWD remains normal in beta thalassemia trait, whereas, in iron deficiency, the RWD is over 15 %.  The confirmation of the Beta Thalassemia Trait requires Hemoglobin electrophoresis.

Beta Thalassemia Trait:

Beta Thalassemia trait is prevalent in India, Mediterranean counties and the North African Arab population. Most of the patients remain symptoms free. Beta thalassemia trait patients are often mistakenly diagnosed with Iron deficiency anemia and are prescribed iron therapy. Iron is not only useless in beta thalassemia but iron overload in men and post-menopausal women may produce liver disease, heart disease and gastrointestinal diseases.

Blood picture of minor and moderate beta thalassemia.

Blood test	minor	moderate
Hb	Low	Lower
Hct	28 -40 %	15 -10 %
MCV	50 -75 fL	40 -60 %
MCH	Low	Lower
Reticulocytes +Target cells + poikilocytes	+	++
Basophil stippling	+	++
Nucleated RBC	0	+
Hb Electrophoresis. Hb A.-alfa2beta2 HbA2.-alfa2 delta2 Hb F.-alfa2gamma2	85 % + 4%+ 2%+	Less than 80% More than 5 % More than 5 %

Beta thalassemia clinically presents as mild or moderate. The degree of deficiency of Beta globin determines the clinical groups.

In mild disease, the patients are asymptomatic almost their entire lives. The hemoglobin level is slightly low. On electrophoresis, the pattern is listed above. These patients need only genetic counseling.

In the moderate beta Thalassemia trait, the anemia is moderate and patients in their adult life show signs of easy fatigue and low capacity of strenuous exercise. The spleen may be enlarged and bone marrow may be hypercellular. There is a much higher rate of RBC turnover, as a result, the bilirubin in serum may be above normal levels. In many cases, periodic blood transfusion is required for anemia. Some patients may require splenectomy.

Association of beta thalassemia and autoimmune disease:

Patients with beta Thalassemia have shown an increased incidence of autoimmune diseases like Diabetes mellitus, fibromyalgia, asthma and arthritis. It is postulated that the location of an abnormal gene in beta thalassemia (11p15.5) is in proximity to immune-regulating eight genes. This association may be a spillover effect.

Another alternative explanation is that when hemoglobin is broken down to hemoporphyrins and hematoporphyrin bind with opioid receptors and act as anti-inflammatory agents. In beta thalassemia, the concentration of hemoporphyrins is low, thereby increasing the chance of autoimmune inflammation.

The increasing numbers of Vietnamese immigrant population found to have Thalassemia E disease. Thalassemia E is due to a different variation of amino acids in the beta globin. Patients are generally asymptomatic but mildly anemic. The hemogram shows a picture similar to the beta thalassemia trait. Genetic counseling is advocated to limit the thalassemia E in the population.

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Iron and Hemochromatosis

 

                                              Iron and Hemochromatosis

                                                 P.K. Ghatak, MD

Iron is an essential element for humans. Iron acts as an electron receptor and donor (redox). The iron is present in the enzyme system in which reduction and oxidation take place. Iron when reacts with hydrogen peroxide (H2O2) releases an oxygen radical that is a poison, and unless H2O2 is neutralized the cells will die. During iron transport and storage, the iron molecule is combined with proteins which makes iron less reactive to cells.

 Most of the iron is present in the hemoglobin. Hemoglobin transports oxygen(O2) from the lungs to every cell of the body.  The mitochondria of the cell utilize O2 for oxidative phosphorylation and the released energy is utilized for cell functions.

Knowledge in Iron absorption, transport, utilization, and storage mechanisms has greatly evolved in the last 10 years, a brief summary will be presented here.

Iron absorption is tightly regulated by a hormone Hepcidin produced primarily by Hepatocytes of the liver, and also by small amounts in the brain. muscles .and other tissues and use locally. 

The amount of iron absorbed varies according to the iron storage status. When the store is full, the absorption may be only 5 %, whereas, in iron deficiency, 35 % of iron is absorbed. Hepcidin is released in response to increased iron of the body. Hepcidin prevents further absorption of iron in the small intestine and in the distal renal tubules.

Iron in the body.

The adult male has 4.5 gm of iron, and an adult female has 3.5 gm of iron in the body. Iron is lost on a regular basis in the female on account of menstrual blood loss and transfer of iron to the developing child during pregnancy.

In premenopausal women, iron storage may be as low as 500 mg. Iron is stored in bone marrow, liver, spleen and in muscles as myoglobin, in tissues in the megakaryocytes. Organic iron ferritin in mitochondria and cytochrome enzyme system acts as a coenzyme. In the blood, in addition to hemoglobin, a small amount of about 4 mg is present as transferrin. Muscles retain iron as myoglobin.

The daily requirement of iron.

Adult female of reproductive age requires 18 mg of iron daily. Whereas, adult males need only 8 mg and children need 15 mg daily.

An individual with normal dietary habits gets about 15 mg of iron in the food. Plant based food containing a good amount of iron is mulberries, fruit, lentils, tofu, potatoes, and spinach. Of the animal source, a high amount of iron is present in red meat, liver, giblets, and egg yolk.

Gastric acid is needed for releasing iron from food. Vitamin C helps iron absorption. Alcohol increases iron abortion. High calcium in the food, zinc, manganese, and excessive amount of tea and coffee decrease iron absorption.

Daily loss of iron from the body is about 1 mg /day in adult males, and about 2 mg a day in females in the reproductive age. Loss of iron is due to the shedding of cells in the GI tract and from the skin.

Hemochromatosis.

Hemochromatosis is due to the overload of the body with iron. The liver is commonly affected. Other organs damaged are the pancreas, heart, skin, gonads, adrenals, pituitary and joints.

There are two distinct groups of hemochromatosis.  One is hereditary and the other is acquired causes.

Hereditary Hemochromatosis.

The gene encodes Hepcidin, the HFE gene. It is inherited by an Autosomal recessive pattern. Two important HFE gene mutations are C282Y (C stands for amino acid cysteine 282 is band location is replaced by amino acid tyrosine Y), and H63D (histidine is replaced by amino acid aspartate)

Hereditary hemochromatosis is clinically classified as type I, type II, type III and type IV. Types I, II, III are inherited as autosomal recessive mode, and type IV is the autosomal dominant mode.

Type Ia Hereditary hemochromatosis.

The mutations are on chromosome 6 and in the C282Y gene known as the HFE gene. Iron accumulation begins in the 20s in male and become symptomatic when reaching 40 -50 yrs. of age. In females, the onset of symptoms is after menopause. The mode of inheritance is autosomal recessive.

Type Ib. The patients have one copy of a chromosome containing the mutated gene C282Y from one parent and another copy of the gene H63D from the other parent. This group constitutes about 2 % of all hemochromatosis patients. Diabetes and fatty liver are common presentations.

Type II. This disorder results in the early development of cardiac symptoms due to iron deposit results in cardiac fibrosis and heart failure.

Type III is a disorder of the Transferrin receptor protein due to a mutation of the TFR2 gene. The severity of symptoms is between type II and type I.

Type IV. In this type, one copy of the mutated SLC40A1 gene that encodes Ferroprotein produces hemochromatosis.

The clinical picture is common in all types of hemochromatosis.

Initial symptoms are nonspecific like fatigue and pain in joints. Later, dark discoloration of the skin, abdominal discomfort, hepatomegaly, and the onset of diabetes mellitus develop. If left untreated, congestive heart failure, cardiac arrhythmias, cardiomegaly and various symptoms due to hypogonadism manifest in young men and in women after menopause. Patients are susceptible to infection by iron-loving bacteria like Vibrio, Listeria and Yersinia.

Diagnosis of hemochromatosis.

Serum ferritin levels over the normal limit of 200 nanogram/ml in adult males and over 300 nanogram/ml in postmenopausal women and ferritin saturation over   45 % in patients with clinical suspicion of hemochromatosis should be confirmed by finding gene mutation by chromosome study. MRI of the liver is not essential for diagnosis but MRI R2/T2 images show the degree of the iron store. The liver biopsy tissue, when stained with Prussian-blue, iron loaded hepatocytes and bile ducts become evident.

 

 Secondary Hemochromatosis.

Secondary hemochromatosis develops when repeated blood transfusions are required for a prolonged period of time. Each unit of blood has 200 to 250 mg of iron. In children, 10 units of blood transfusion can overload the body with iron and in adults, 20 units will do the same. In iron overload conditions, the blood levels of ferritin reach over 1000 micrograms/ L.

Type of anemia where repeated transfusion is necessary.

Thalassemia, Myelodysplasia, Chronic hemolytic anemia, Acquired bone marrow aplasia, Multiple myeloma, Acute leukemia, Lymphoma, and Chemotherapy induced bone marrow depression.

To prevent iron overload, a Chelator Agents is used. At present three agents are approved for use in secondary hemochromatosis.

Deferoxamine. Deferoxamine is given IV, and the dose is 25 -50 mg/ Kg body weight. It used to be commonly used but now it is not. IV infusion site pain and infection are the main reason the compliance is poor.

Deferiprone. Deferiprone is given by mouth, the dose is 75 mg/ Kg body weight, and the drug must be given in 3 divided doses. The main adverse effect is agranulocytosis. The patient's compliance is good with deferiprone.

Deferasirox. Deferasirox is also an oral drug, given only once a day, the dose is 10-30 mg /Kg body weight. GI symptoms are a major side effect, and compliance is also good. At present, it is frequently prescribed chelating drug.

The goal of Chelating agent therapy is to bring down Ferritin levels to the normal range.

Complications:

In hereditary hemochromatosis: enlarged liver, enlarged spleen, cirrhosis of the liver. hepatocellular carcinoma, arthritis, impotency in males, early menopause in females, enlarged heart, cardiac arrhythmias, congestive heart failure, hypothyroidism and dark skin.

Prevention of Hereditary Hemochromatosis.

Hereditary hemochromatosis: Genetic counseling.

Diet.

 The patients should avoid oysters and clams in order to avoid infection by iron loving bacteria.

Treatment of Hereditary Hemochromatosis.

Phlebotomy. Patients are required to undergo phlebotomy once a week until the blood ferritin reaches near normal levels. Maintenance phlebotomy is generally required, on average, 2 to 3 times a year to keep the ferritin levels in the normal range.

In hereditary hemochromatosis, chelating therapy usually is not required.

Prognosis.

In early detected cases the life expectancy should be normal. In late detected cases the prognosis varies according to the degree of damage to organs and the organs involved.

written in memoriam of classmate Rama Mukherjee. 

edited: August 2025.

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Fighting with a Killer. ( Lung Cancer)

                                                                    Lung Cancer

                                                             PKGhatak, MD

Lung cancer is a fatal illness. Incidence and deaths from lung cancer are steadily increasing in developing parts of the world, as they did in the West after the end of WWII, and the incidence of new cases of lung cancer is directly related to cigarette smoking and industrialization with the degradation of the environment.

Basically, there are two classes of lung cancers.

1. Small cell lung cancer.

2. Non-small cell lung cancer. (NSCLC)

The above classification is based not only on the pathological features of the cancer cells but also applies to symptomatically, tumor spread, response to therapy and prognosis.

Susceptible population.

Adults with a long history of cigarette smoking, working in places where air or soil or water is contaminated with radioactive elements, those who are carriers of BRACA 2 gene, survivors of leukemia and other malignancy, and those who received chest radiation, people receiving immunosuppression therapy following organ transplants or having autoimmune diseases are susceptible for lung cancer. Incidents are also higher in patients with a certain type of pulmonary fibrosis and scar tissue in the lung. Exposure to radon gas and asbestos are recognized risk factors. Exposure to heavy metals, specially arsenic, is carcinogenic. A higher incidence in Sarcoidosis is a risk factor.

Symptoms at the time of Presentation.

Patients may not have any symptoms and cancer is incidentally detected when a chest X-ray was taken for other reasons. In the early stages, in symptomatic patients, an unproductive cough is usual. Some patients develop asthma for the first time in midlife. Some patients seek help when they cough up bright red blood. Other symptoms are as follows. -  Feeling vague symptoms of not feeling well, unintended weight loss, hoarseness of voice, lump in the neck area, weakness of large muscle groups of hips making getting up from bed or chair difficult and then the weakness of shoulder muscle limits patients' ability to raise hands overhead - Lambert-Eaton syndrome. Unexplained neuritis of one or more peripheral nerves in different parts of the body. Pain over spinal bones or ribs. Some have convulsions as the first presenting symptoms. Clubbing of fingers, pretibial edema and tenderness over lower tibial bones. Deep vein thrombosis,  neuromusculopathy, peripheral neuritis and dermatomyositis are also presenting symptoms.

Special features of Small Cell Cancer. 

Small cell carcinoma is only 15 % of the total lung cancer population. Under the microscope, the cancer cells resemble carcinoid cells. There is a very strong correlation with cigarette smoking. Patients are often male and in the middle aged group. The common symptom which brings them to doctors is chest pain, which is often mistaken for heart attacks or angina. Initial routine chest x-rays often appear normal. Either by CT scan of the chest or very expert radiologists can detect a faint outline of a tumor on chest x-rays, located on the upper lobe of the lung and in the hilar region.

Early hilar lymph node enlargement produces pressure symptoms on the local structures. As more tissues are infiltrated by tumor cells, and more symptoms develop this is called Thoracic Inlet syndrome, the symptoms of Thoracic Inlet syndromes are A. 1. Inferior cervical ganglion and paravertebral sympathetic chain infiltration by cancer cells produce a dropping of the upper eyelid with 2. a small constricted pupil and 3. loss of sweating on the involved side of the forehead. This symptom complex is called - Horner syndrome.

 B. Pain in the arm and forearm in the distribution of brachial plexus nerves.

 C. Superior vena cava obstruction producing edema of head and neck, bluish discoloration of face, distended conjunctival vessels.

 D. Infiltration may include the phrenic nerve producing paralyzed hemidiaphragm.

E. Infiltration of apical pleura may produce pruritic chest pain and pleural effusion.

Paraneoplastic syndrome. The small cell cancer cells and rarely alveolar cell cancer, at times, secrete hormones like polypeptides and produce a variety of symptoms. A few of them are mentioned here.

Cushing's syndrome is due to excess ACTH secretion. Hyperparathyroidism produces high serum calcium and symptoms related to it. TSH like hormone secretion leads to thyrotoxicosis. Insulin like hormone produces severe hypoglycemia. Melanin like peptide producing Acanthosis nigricans - dark pigmentation of skin in intertriginous areas and the flexural surface of limbs. Severe hyponatremia due to inappropriate antidiuretic hormone production (ADH) causes excess free water reabsorption in renal tubules.

 Tumor cell behavior.

Tumor cells spread early and often by the bloodstream to the brain and bones.

Biopsy.

Fine needle aspiration biopsy under ultrasound guidance yields good results. Often bone marrow biopsy is required for diagnosis and staging. The cancer cells are small and rounded with a thin margin of peripheral cytoplasm, and coarse chromatin without a nucleolus. The cytoplasm contains neurosecretory granules in 90 % of cases. No immunological staining is possible. 

Treatment.

In the localized early stage of the disease, chemotherapy containing Cisplatin or Carboplatin and Etoposide followed by cranial radiation is recommended. In widespread diseases, a combination of chemotherapy and chest radiation therapy is followed by cranial radiation. No immunotherapy drug has any role in the treatment of small cell cancer.

 

Prognosis.

The 2-year survival rate in late presentation is disappointing, only 2 to 5 %, and 20 to 40 % in early cases.

Non-Small Cells Lung Carcinoma (NSCLC).

 

This group contains Adenocarcinoma, Squamous cell carcinoma, Large cell carcinoma, alveolar cell carcinoma, and others.

 

Special features of NSCLC.

85 % of all carcinomas of the lung fall into this group, and adenocarcinoma leads this group.

Nonsmokers and smokers, unfortunately, are both susceptible to Non-Small Cell cancer of the lung. Malignant transformation of squamous dysplasia, a common occurrence in smokers, into squamous carcinoma is a usual occurrence. Adenocarcinoma may develop from preexisting scars. Delayed clearing of pneumonia, bloody sputum, or associated pleural effusion may be the presenting symptoms. High serum calcium is often seen in squamous cell carcinomas from osteolytic bone metastasis. Seizures from single brain metastasis are seen in adenocarcinomas. Early metastasis via blood is common in adenocarcinomas. Hypertrophic Pulmonary Osteodystrophy (HPO) is often seen. The HPO is characterized by burning pain and red discoloration of the skin over the tibia and knees, edema, clubbing of fingers, and tender wrists and fingers due to subperiosteal new bone formation. Squamous cell carcinomas are usually centrally located and produce hemoptysis. Adenocarcinomas are usually located in the peripheral zones, and arise from mucus glands and or from the epithelial cells of terminal bronchioles.

Alveolar carcinomas are included in the adenocarcinoma group but it has some distinct features - generally have multiple sites of origin, patients have vague symptoms that can go on for a significant time period, patients often develop neurological symptoms or psychological problems. The diagnosis is often delayed because sputum examinations generally are free of cancer cells and the tumors are not accessible to bronchoscopic view. A lung biopsy is required for diagnosis.

Large cell cancers are rapid growers, maybe central or peripheral in location.

 

Diagnosis.

Bronchoscopy and bronchoscopic biopsy of the lesion are preferred. If the tumor mass is not accessible by bronchoscopy, then ultrasound guided fine needle aspiration biopsy is recommended. In cases where hilar lymph nodes are present,  suprasternal mediastinoscopy is preferred for biopsy and staging.

Immunohistochemical staining of biopsy helps the identification of cell types and subtypes.

The initial diagnosis is followed by the detection of mutation genes or genes which have great importance in the treatment with immunotherapy and the use of immunotherapy improves survival.

 

Treatment.

Surgery is the preferred treatment modality in all cases of NSCLC wherever possible. Surgery is followed by chest radiation therapy in localized disease without lymph node involvement.

In the case of lymph node involvement or evidence of distant metastasis Chemotherapy and radiation therapy are added after surgery. Chemotherapy agents are Platin based, most institutions follow their own protocols but all protocols include platins.

Prognosis of NSCLC and Immunotherapy.

The patients live 2 to 5 years following surgery and when combined with chemotherapy and /or radiation, patients may live an additional 10 to 24 months.

Immunotherapy has added a new line of cancer therapy with good to excellent results in patients who were deemed too far advanced or did not respond adequately to surgery and chemo-radiation therapy.

Immunotherapy:
Epidermal Growth Factor Receptor blockers, Tyrosine Kinase blockers, PD1, PD-L1 antibodies, CTLA 4 receptor blocking antibodies are available. These are briefly mentioned here.

Epidermal Growth Factor (EGF) – EGF is a protein first detected in the submandibular salivary and parotid glands. It promotes tissue repair, cell growth, and wound healing of the mouth, stomach and intestine. Subsequently, a group of proteins, similar in structure and functions, was also found in many other tissues including immune cells. EGF binds with its receptors on the cell surface and then induces Tyrosine kinase, a key to the cell division, growth, and development of normal tissue. The gene that controls EGFR (epidermal growth factor receptor) can mutate and this leads to greatly increased receptors on the cell surface that result in excess cell growth. This is particularly seen in some cases of non-small cell cancer of the lung. Antibodies to EGFR are now available for treatment. The antibodies block EGFR receptors present on the cancer cell surface and prevent binding with EGFR and thereby preventing the progression of cancer.

 

Program Cell Death Protein 1(PD-1) is another cell growth regulating protein. This is a surface protein abundant on the T cells surface. When it binds with its receptors, it down regulates immune response to foreign agents or cancer cells. Another transmembrane protein is Programmed death Ligand 1 (PD-L1). When PD-L1 binds with PD1 receptors, it performs dual functions. 1. reduces antigen-specific T cells in lymph nodes. 2. decreases apoptosis (programmed cell death) of normal T cells. Thereby reduces immunologic reactions. Non-small cell cancer of the lung has a rich supply of PD-L1 receptors and thereby evades Killer T cells and cancer progresses unchecked.

 

CTLA4 (cytotoxic T lymphocyte protein 4) is also called CD152, is a protein receptor, when it binds with CD80 and CD86 it down regulates immune reactions and when it binds with CD 28 it up regulates immune responses. Blocking antibody is available against CTLA4 and when combined with PD1 or PD-L1 antibody therapy the results are much superior to those used alone.

Unfortunately, immunotherapy also has adverse side effects. The immune cells can attack the skin, lungs, liver, nervous system, heart and kidneys and other organs. In such an instance, the immunotherapy has to be terminated.

 

Prognosis of non-small cell Lung Cancer.

The prognosis of lung cancer is not good. The 5-year survival is 18 %. Immunotherapy has greatly improved survival time in those who have the appropriate mutation of a gene/ genes.

 

In the August 13, 2020 issue of the New England Journal of Medicine, an article on lung cancer clearly shows the declining incidence of lung cancer since 2001 and more impressively is the decline in the death rates. In the case of NSCLC, these results are due to the combined effects of decreased cigarette smoking in the USA population and the availability of immunotherapy drugs. The rate of decline of death rates nearly doubled from 2013 to 2016 when compared with the decline rate of new cases of lung cancers; conforming to the effectiveness of immunotherapy. In the case of small cell carcinoma, the decline in mortality is entirely due to a decrease in cigarette smoking, since immunotherapy for small cell cancer is not available.

In recent years, far advanced lung cancer cases many centers are treating patients with Chemotherapy plus Immunotherapy without looking into PD1 or other gene mutations. This practice is now extended to Small Cell cancer patients also. According to them, this combination showed improved survival time. However, it should be noted it is a palliative treatment.

If nothing else can convince you, this study should. Do not doubt the benefits of giving up cigarette smoking. If you want to live a long life, this gives you one more chance. As an ad for satellite TV says " so, what are you waiting for"

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Mutation of Genes and Psoriasis

 

                                   Genetic Mutation and Psoriasis

                                            PKGhatak, MD

Every function of the cell, from the time of conception to the very end of life, is guided by the instructions inscribed in the genes. These functions can be grouped as Innate, adaptive and aberrant.

The skin is a large and special organ. It is entirely exposed to the elements of the outer world (except the parts we intentionally keep covered by clothing). The surface layers of the skin must be replaced at a constant and consistent rate as they are lost and that is the Innate function; some of the cell functions have to be modified according to the changes in the external environment and changes in the body from infections, other diseases or nutritional causes and these are adaptive function. The aberrant functions are due to the mutation of genes and Psoriasis is one of them.

In psoriasis, the cells of the surface layer of the skin grow at a rapid rate and the new cells accumulate over the older cells before the old cells have time to fall off. The accumulated patches are called Plaques. Inflammatory cells infiltrate the skin and underneath the plaques, the blood vessels multiply in numbers, causing an increase in the blood supply, producing itching. The top layer of dead cells of the plaques appears as pale white to silvery flakes and dandruff on the scalp and is shed off easily. These plaques may be present over the elbows, knees, lower back, scalp and face. It may appear as pink or red scaly drop like lesions in children and is known as Guttate psoriasis. Plaques underneath the breasts, buttocks, and groins are called Flexural psoriasis. In some cases, the entire skin is covered with dead loose cells and the color of the skin turns red from the increase in blood supply and this is called Erythrodermic psoriasis. Lesions on palms and soles of feet appear as pustules called Pustular psoriasis. Psoriasis also affects nails and joints and is called psoriatic arthritis.

Study methods.

Study of families of multiple members affected by psoriasis, studies of affected twins, and analysis of whole genome for the presence of mutations of genes in psoriasis patients, methylation of genes which modify gene functions without altering DNA sequence are commonly employed methodologies to investigate the role of hereditary and or phenotype mutation of genes in psoriasis.

The mutation of gene/genes in T-lymphocytes and B-lymphocytes leads to altered functions of Interleukins and Cytokines. These interrelated changes ultimately alter the rate of cell divisions and programmed cell deaths, inflammatory responses and generate autoimmune diseases.

Over 80 mutated genes are associated with psoriasis. However, the genetic mutation in psoriasis is not more than 20 % of all cases of psoriasis. The cause of the rest is unknown. Investigators advanced various theories from poison to pollution of the environment but definitive evidence is lacking.

Reports from Saudi Arabia indicate 5 % of the adult population suffers from psoriasis. The prevalence of adult psoriasis in China is 0.5 %, in Norway-11 %, in USA -3 %, black to white- 3 to 1 ratio, in India -2%, in Western Europe -3 %, and in Latin America 2%.                 

Known gene mutation.

Mutated genes associated with psoriasis are called PSORS and are designated 1 through 9 numerically. These genes are present on Chromosomes 1 to 22, of which frequent mutation was seen in chromosomes nos.1.6,9,17 and 19. These mutations may be at one locus or in multiple loci. In the Chinese population, the mutation of genes on chromosome 1 is most frequent, in Europe, the mutation is frequent on chromosome 17. Studies in Saudi Arabia show autosomal dominant inheritance with mutation of a gene on chromosome 17q25 (on the long arm of chromosome at band location 25) and q4 loci.

Human leukocyte antigens (HLA) B-13, B-17, B-57, and CW6 are associated with psoriasis. About 70 % of HLA mutation is due to HLA CW6.

Interleukin-36 amplifies TH-17 lymphocytes.

Gene-wide association (GWA) identified 16 loci. CD4 helper T cells and CD8 cytotoxic T cells are associated with psoriasis.

Genetic mutations alone may not themselves be the cause of psoriasis, but in association with additional factors, are responsible for psoriasis. Publications from WHO indicate infections, poisonous agents in the air and water, stress, obesity, cigarette smoking, and concurrent autoimmune diseases, such as Crohn's disease, are triggering factors. All these factors, namely genetic predisposition, and hereditary and triggering factors, lead to internal changes in the body and lead to the development of the chronic inflammatory autoimmune disease - psoriasis.

 

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Cholera and Calcutta (Kolkata)

                                                Cholera and Calcutta (Kolkata)

                                                 PKGhatak, MD

In 1964, I disembarked at the international terminal of the Cairo Airport in Egypt as a transit passenger. The instant the officer saw the alcutta address on my passport, he asked me to produce a cholera inoculation certificate and his body language told me as if I was going to give him cholera at that moment. Until that moment, I did not know that a stigma was attached to Calcutta as the birthplace of the cholera pandemic.

The first pandemic originated in 1817 in a town called Jessore (যশোর) near Calcutta, which now belongs to Bangladesh. Since then, five more pandemics of cholera followed and all those pandemics began in and around Calcutta. The seventh cholera pandemic, however, started in Indonesia.

It is also fitting that a fundamental understanding of the parthenogenesis of cholera and an effective treatment modality also came from Calcutta. Pathology professor Dr. Shumbhunath Dey of Calcutta University discovered cholera toxins in 1951. The endotoxin not only prevents sodium chloride absorption but also destroys the enterocytes of the small intestine, resulting in pouring into the gut lumen, a massive amount of water, electrolytes and bicarbonate from the blood and intestinal tissues. That amount of blood volume loss in the small intestine results in “Rice water” diarrhea and severe dehydration. Dehydration leads to shock and death. Professor Dey also found another cholera toxin called exotoxin, which was antigenic, heat-labile, and had no enzymatic action. He used rabbits as the animal model to study cholera. Recent advances in molecular biology have made it possible to define clearly how endotoxin acts on the intestinal cells and opens up pores that pump out water and electrolytes into the intestinal lumen. Endotoxin activates the adenylate cyclase enzyme, which then increases cAMP, resulting in the opening of pores.

Dr. Hemendranath Chatterjee of Chittyaranjan Hospital in Calcutta developed the Oral rehydrating solution for combating dehydration, which cut down the death rate of cholera to 3% from 30%. His oral rehydration solution contains 1000 ml of sterile water, 2.6 gm of sodium chloride / common salt substitution allowed, and 25 gm of glucose /sugar if glucose is not available. The current oral rehydrating powder has a different formulation with the addition of citrates/ bicarbonate, potassium and a balanced osmolarity matching the human tissue.

A typical case of cholera.

Cholera is an infectious diarrheal disease. Children are specially vulnerable because of the lesser amount of acid present in their stomachs; adults on gastric acid blocking drugs or antacids are susceptible to infection. Contaminated drinking water is a common source of cholera, but eating contaminated raw fruits and vegetables, and undercooked shrimps, crabs, prawns, lobsters, oysters, etc., are common in endemic areas. The number of V. cholerae ingested, in an epidemic, may be as high as 100,000/ ml. If the bacteria survive the gastric acid bath in the stomach and enter the small intestine, then the vibrio quickly moves past the mucus layer of the small intestine by the flagellar movement and attaches to the intestinal cells. Once the V. cholerae enters the cells, the endotoxin quickly produces symptoms. Symptoms usually start within a few hours but may be delayed 24 to 48 hours. The first symptom is the onset of watery diarrhea, which quickly turns into frequent voluminous rice-water looking stools, often with a mild fishy odor, and patients begin to vomit. Patients become dehydrated, weak and prostrated; the color of the skin turns yellowish pale to light blue. If treatment is not available immediately, shock soon follows.  Patients usually do not have a fever and may complain of abdominal cramps from the distended small intestine with watery fluid accumulation. Death comes early and in earlier times, it was called Blue Deaths. Mortality without treatment is over 50 % or higher. Diagnosis is easy in an outbreak; if in doubt, a stool examination reveals numerous Vibrios, a rapid test kit, the Crystal VC dipstick is available, and the confirmation requires stool culture.

In Indian Sanskrit literature, Sushruta Samhita, written at the time of Buddha, a disease was recorded called Visuchika, now we call the same disease cholera. Hippocrates, 460-377 AD, described the illness as cholera, the word derived from the Greek word, bile. In Calcutta, cholera was called Olautha (an act of vomiting and purging). Portuguese sailors who sailed between Gujarat ports in west India and Europe learned the name Mordezin from the locals. Arabs called it Haida and the Chinese it Huo Luon.

Important events in cholera pandemics.

The name Asiatic Cholera was introduced at the time of the second pandemic, which raged between 1829 and 1837. The 3^rd pandemic of 1852 killed 1 million Russians. The pandemic of 4^th between the years 1865 - 1866, which hit Zanzibar very hard, resulted in the death of 70,000 people. Zanzibar is now in Tanzania. In the years between 1881 and 1896, the 5^th pandemic, cholera, reached South America for the first time. India suffered the most deaths, about 800,000, during the years 1899 and 1923 during the 6^th pandemic. The last pandemic began in 1961 in Indonesia and is still going on. Following the earthquake in Haiti, a cholera epidemic began in crowded shelters and killed 10,000 people, and in Yemen, during the civil war in 201,5, about 2000 refugees died of cholera.

Other milestones in combating the cholera pandemic.

In 1832, Dr. Thomas Latta of Scotland introduced an IV saline solution to combat dehydration. Filippo Pacini of Italy in 1854 detected and demonstrated the Cholera organism – Vibrio cholerae. Dr. John Snow of London, England, documented the origin of the Cholera epidemic of 1954 in Soho, London, from raw sewage contamination of drinking water wells, and initiated control of cholera by supplying safe water. Dr. Robert Koch isolated Vibrio cholerae from the stool of cholera victims of the Egyptian cholera epidemic in 1883 and established Vibrio cholerae as the causative organism of cholera. In 1879, an effective cholera vaccine for chickens was developed by Louis Pasteur of France. The first human cholera vaccine was introduced in Valencia, Spain in 1885 by Jaume Ferran. A virulent new biotype of cholera Vibrio called El Tor was identified in 1935 in Celebes, Indonesia. In 1948, the antibiotic Tetracycline was demonstrated to kill Vibrio cholerae and introduced for the treatment of cholera. Subsequently, Erythromycin and doxycycline were approved for cholera treatment in 1952 and 1967, respectively. Bactrim proved to be equally effective in controlling cholera in 1968. Currently, no antibiotic is required for the treatment of cholera. Ondansetron, an antagonist to Serotonin, was used to control diarrhea in cholera effectively. An oral cholera vaccine, Dukoral, was approved in 1991. Another serotype of El Tor O139 cholera was detected in Bangladesh. (O stands for somatic antigen). In 2007, Japan incorporated a cholera gene into the rice grains and used engineered rice to control cholera. In 2009, the Indian Stantha Biotech company introduced a vaccine named Sanchol, which incorporated both O1 and O139 serotypes of Vibrio cholerae.

Some special features of Vibrio cholerae.

 Vibrio cholerae is a gram negative, curved-shaped rod, measuring 1 to 3 micrometers by 0.5 micrometers, having a single flagellum from one pole, and is very mobile in liquid medium. It is a marine and brackish river water organism. Humans are the only known reservoir but shellfish, crabs, shrimps and vegetation in coastal mangrove forests are heavily contaminated with Vibrio. Vibrio belongs to the Vibrionaceae family and also exhibits some features of Pseudomonas and Enterobacteriaceae. Vibrio is a facultative anaerobe. Since Vibrio is a marine organism, it requires 2 to 3 % sodium chloride for growth in artificial media. In a solid medium, V. cholerae develops numerous lateral flagella and becomes much less mobile. Vibrio does not produce spores and reacts positively to oxidase. Vibrio is the most abundant bacterium in water. Only V. cholerae and V. parahaemolyticus are pathogenic to humans.  V. vulnificus can cause wound infection, gastroenteritis and septicemia in humans. V. fetus, now called Campylobacter jejuni, may cause dysenteries like gastroenteritis and CNS infection. Helicobacter pylori are closely related to Vibrio and H. pylori is often the cause of duodenal, gastric ulcers, and gastric cancer.

The classic V. cholerae is serologically O1. El Tor subspecies subsequently morphed into a new stereotype, O139 in Bangladesh in 1992. Gradually, El Tor O139 became the main Vibrio responsible for cholera in the Indian subcontinent, the Philippines, and Indonesia. Antigenically O139 is completely different from the O1 serogroup. People in the endemic area have no immunity against O139. El Tor O139 is more virulent and prevalent in humans as carriers at a rate of 1: 30 -100. Whereas, the carrier ratio in V. cholerae O1 is 1: 2-3. The El Tor also survives longer in extraintestinal sites.

Calcutta.

Today, Calcutta is a megacity in India. But it had a very humble beginning. The British East India Company arrived at the Mughal court in Delhi in 1608. Job Charnock, an employee of the East India Company, came to Calcutta in 1690. Then Calcutta was a sleepy little village called Sutanatti. The East India Company established a trading post on the east bank of the Hugli River, 120 miles upstream from the Bay of Bengal. A pristine Mangrove Forest, Sundarbans (beautiful forest), was present along the entire Bengal coastal area of the Bay of Bengal. That mangrove forest was also the habitat of Vibrio Cholerae. Between the Surdarban and Calcutta, there were mainly swamps. The East India Company obtained “Letters of Patent” in 1698 from the Mughal emperor, which gave them the authority to collect revenue from the local population. In 1756, a war broke out between the East India Company and the Bengal province Mughal ruler Siraj-al-Dawlah. In 1757, Siraj-al-Dawlah was defeated in a so-called war, and he was assassinated while in custody. Subsequently, the British took over the administration of the entire Bengal province. In 1772, Calcutta became the capital of British India.

As local people started to settle in and around Calcutta, swamps were drained for agricultural use and other parcels of swamps were covered by fisheries. The king of Sundarban was the Royal Bengal Tiger. Local people did not venture into the forest because of the fear of tigers, except during the fishing season, at the time of the Shad running upriver for spawning. Gangetic shad (গঙ্গা ইলিশ) is a local delicacy and in high demand in Bengal. 

British hunting parties used to employ Sepoys (local foot soldiers) to scare the tigers by beating drums and driving the tigers toward the hunters sitting with their guns on a high platform built for the occasion. A single hunting party killed 100 or more tigers. As the tiger population decreased, the chance of encountering tigers became less; and more locals began to invade the forest frequently. Now, humans began to come in contact with Vibrio cholerae in higher numbers. Local people had acquired immunity, but the new people that came to the area had no immunity and local outbreaks of cholera became an annual event.

In 1817, an outbreak of cholera in Jessore, a town not far from Calcutta, got out of hand and cholera became a Pandemic.

Chlorination of Calcutta water supply.

The Calcutta corporation began chlorinating water in 1905 for residential and business uses, but also continued to supply unfiltered and unchlorinated water for cleaning streets and fire hydrants. Yes, the streets of Calcutta and the pavements (footpaths) were washed clean at the crack of dawn each morning, and gaslights were turned off at the same time. Each summer, cholera broke out locally until a team of experts from the WHO arrived in Calcutta in 1952. They recommended chlorinating unfiltered water, and after the chlorination of the unfiltered water was implemented, the local outbreak of cholera nearly completely disappeared from the slums (baste) of Calcutta. Calcutta, being known as a Cholera city, the Indian Council of Medical Research set up its Cholera Research Centre (later named as the National Institute of Cholera & Enteric Diseases). In recognition of the excellence in research, the W.H.O. established its WHO-International Reference Centre for Vibrio.

 The advances in medical science in the last 50 years are nothing but spectacular and the degradation of the environment is nothing but disastrous. Many have pointed out that the COVID-19 pandemic is a wake-up call. There have been many wake-up calls before and COVID is not going to be the last one. The special interest groups, those who have degraded the environment, are not going to fade away easily. Progressive human encroachment in forested areas, wetlands and seas has disturbed the balance between plants and the animal kingdom and diseases unknown to humans are exploding disastrously. The cholera pandemic is just one such incident.

edited June 2025

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