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

********************************************************

 

Idiopathic Pulmonary Fibrosis

 

                                                   Pulmonary Fibrosis

                                                   PKGhatak, MD

Pulmonary fibrosis is a pathological term indicating the presence of abundant fibrous tissue in between the alveoli (air sacs) of the lungs. This entity is not just one condition but more or less 200 different conditions/ diseases that are included under this broad definition.

In the interest of patients, Pulmonary fibrosis may be considered just two entities. 1. Unknown causes. 2. Known or secondary to another illness the patient is suffering from or had suffered recently.

Unknown causes of Pulmonary Fibrosis are called Idiopathic Pulmonary Fibrosis or IPF in short. In this article, an attempt will be made to summarize updated information on IPF.

The current COVID pandemic has generated fear, interest, discussions on infections, immune responses, overactive immune system, resulting in a Cytokine storm, pneumonia, and the cause of death of unfortunate patients. The public has already acquired some information about them.

The protective system that keeps our body free of infections, cancers, parasites, etc., also has another important function, which is to repair the damaged tissue and make the body whole again.

The repair of damaged tissue is undertaken in stages. In the initial stage, the dead cells and other foreign agents are removed from the site, then in the next stage, the damaged parts are stitched together by laying down fibrous tissue, like we repair torn fabrics with threads. And the final stage is the remodeling of the damaged site involving laying down various tissues by the respective Stem Cells.

In Idiopathic Pulmonary Fibrosis, the final stage does not happen, instead, the fibrous tissue keeps growing. This fibrous tissue has very little elasticity, unlike the healthy elastic tissue of the lung. We breathe in the air by expanding the chest wall unconsciously without effort by contacting the diaphragm and a group of breathing muscles. The fresh air from outside, which is rich in oxygen, enters the lungs and travels to the tiny air sacs, called alveoli. Carbon dioxide leaves the blood and oxygen enters the blood. Then inhalation stops, the lungs return to the initial state by the pull of the elastic tissue of the lung and the carbon dioxide containing air is forced out of the lungs.

Fibrosis of the lung disrupts this smooth respiration and the exchange of gases. More effort is required to inhale and exhale. Breathing becomes a laborious effort, the patients generally refer to shortness of breath.

What is the incidence of IPF.

In the USA, the incidence is about 8 per 100,000 people per year, and the estimated worldwide rate is 20 per 100,000 people /year.

Is IPF a hereditary disease.

In general, IPF is seen as just one person in a family. When more than one person in a family has identified this disease, then the illness is called Familial IPF. The incidence of Familial IPF is about 5 % of all IPF cases.

What are the known mutations of the gene/ genes or abnormal DNA of the chromosomes.

This field is expanding. As of now, in about 15 % of cases of IPF the TERE and TERT gene mutations are documented. These mutated genes are located in the telomeres of Chromosomes. As a result, the Telomerase enzyme decreases. In the end, the alveolar cells die and an increase in fibroblasts occurs. The fact that IPF patients are over 50 years of age when they notice shortness of breath supports this. It is postulated that the mutation of genes begins initially with a few genes and as time passes, the population of mutated genes increases and the changes in the lung become significant enough to produce symptoms.

What are the presenting symptoms.

The most common symptoms are shortness of breath and persisting dry cough. Later on, breathlessness develops even at rest. Fatigue, decreased appetite and weight loss follow.

What physical abnormalities were detected by examination.

The findings are: rapid rate of breathing, clubbing of fingers, bluish nail beds and lips, dry rales also called crackles detected by listening with a stethoscope over the bases of lungs. In more advanced cases signs of right ventricular hypertrophy and congestive heart failure are present.

 What other names of IPF were used before.

In the past IPF was called Hammond-Rich syndrome, Cryptogenic fibrosing alveolitis, Chronic idiopathic fibrosing alveolitis, Usual pulmonary fibrosis, immune pneumonia, desquamating interstitial pneumonia and now it is simply known as IPF.

What tests are considered diagnostic.

Until recently, an open biopsy of the lung was required for a definitive diagnosis. A high-resolution CT (HRCT) demonstrating typical radiological findings and absence of other radiological signs of specific illnesses, in a clinical situation, consists of patients over 50 years of age, presented with symptoms and signs listed above. This is enough to make a firm diagnosis of IPF. Lung biopsy is called for only when this method fails.

What are specific signs detected in HRCT.

The disease preferentially involves the lower lobes of the lung, and the degree of changes is variable from one location to the other, even varies within a given section. Changes begin in the distal parts of the lung and then spread toward the central part of the lung. Septal thickening, honeycombing pattern, traction bronchiectasis, subpleural and basal reticulations are diagnostic for IPF.

If a biopsy is performed, what are the diagnostic findings.

The pathological changes are variable because of the nature of IPF. However, these changes are present: alveolar cell damage, accumulation of fibroblasts, contraction and collapse of alveolar architecture, deposition of collagen I, collagen III and fibro mucin deposition in the extracellular matrix.

Why is bronchoscopic biopsy of the lung not advocated in IPF.

The tissue obtained in bronchoscopic biopsy is tiny, a larger piece of the lung is necessary for proper examination because of non-uniform pathology. Post biopsy pneumothorax generally follows because the lung is stiff and fails to contact and seal the opening made by biopsy.

Why does right ventricular hypertrophy and congestive heart failure develop in IPF.

The right ventricle pumps out blood into the lungs via the pulmonary artery - one to the right and one to the left lung. The distortion of pulmonary architecture causes blood vessels to twist and the lumen becomes narrow, which causes obstruction of easy blood flow to the lungs. Vascular resistance increases. This is called pulmonary hypertension. The hypertrophy of the right ventricle is just an attempt to increase the force of contraction to overcome pulmonary hypertension. When this compensatory mechanism fails, congestive heart failure develops.

What are the fundamental abnormalities in IPF.

Leukotrienes (ILs), Prostaglandins (PGs) and Cytokines are important in the development of IPF. Many previously accepted theories, in the genesis of IPF, are discarded. Today the theory, that most researchers agree with, is highlighted here:

For reasons unknown, the alveolar type I cells die prematurely and steadily. The type II alveolar cells proliferate to cover the exposed basement membrane. In IPF, the alveolar type II cells do not disappear, as type II cells should do in normal repairs. Instead, type II cells recruit Macrophages which in turn recruit fibroblasts and transform them into myofibroblasts. Myofibroblasts secrete collagen. In inherited cases, the DNA gene mutation encodes a defective protein, Surfactant C, an unfolded protein. The mutated genes are located in the Telomerase coding areas. This protein also limits cell repair. The CD4TH1 cells stimulate the Macrophages of the lungs to transform into macrophage1 cells (M1). M1 expresses IL-12(interleukin-12), TNF (tissue necrosis factor) and Chemokine CXCL10. All of these lead to tissue destruction. In acquired IPF, the mutated gene preferentially stimulates CD4 helper T cells (CD4TH2) cells which in turn stimulate the growth of immune response cells and not the inflammatory cells. CD4TH2 cells stimulate the production of macrophage 2 cells (M2) that lead to the production of IL-4 and IL-13. Both are stimulants to fibroblast proliferation and angiogenesis.

What other IL (Leukotrienes) influence IPF.

IL-13 is an important mediator of pulmonary fibrosis. IL-1 contains 11 subunits, 4 of them act to suppress inflammation, whereas the remaining 7 are proinflammatory.

Role of Prostaglandins (PGs) in IPF.

PD E2 normally inhibits fibroblast proliferation and its migration to the lungs. Also decreases collagen secretion and limits growth factor (TGF beta). In IPF the signaling of PD E2 is downgraded as a result, fibroblast activities are not restricted. Prostaglandin D2 expresses the COX2 enzyme which enhances IPF.

Role of Cytokines in IPF.

The role of cytokines in IPF is complex. The balance between pro-inflammatory cytokines and profibrogenic cytokines is tilted in favor of angiogenesis and fibroblast proliferation. The pro-inflammatory cytokines are CCL17, CCL22, CCL2, and CCL3. The proangiogenic cytokines are CXCL8, CXCL5, and CXCL12 and antiangiogenic are CXCL9, CXCL10, and CXCL11. CXC chemokine is thought to promote aberrant neo-angiogenesis and lung recruitment of circulating fibrocytes, with the contribution of TGF-β. 

The fibroblast proliferation and extracellular matrix deposition induced by TNF-α include interleukin (IL)-1α, IL-1β, and TGF-β. All these cytokines exert their effects on lung fibroblasts through induction of the secretion of platelet derived growth factor PDGF. The platelet derived growth factor PDGF and connective tissue growth factor CTGF is the final movers in fibroblast recruitment and proliferation and in the end the alveolar cell proliferation and myofibroblast generation and collagen deposition in the matrix. 

What other tests are performed in IPF.

Two sets of tests are obtained before starting the treatment of IPF.

The first one consists of determining the lung volumes, diffusion capacity and pulse oximetry.

The other tests are a battery of tests to exclude any treatable disease that was overlooked at the time of final diagnosis. That part of the tests is left out in this discussion.

Lung volumes and diffusion capacity.

The vital capacity, total lung capacity, inspiratory reserve volume and functional residual capacity are all reduced. These tests are known as Pulmonary Function Studies. These pretreatment numbers are used for monitoring the disease. The diffusion capacity test is an indication of the severity of the functional consequences of IPF. Subsequently, repeated diffusion capacity tests are not necessary, that can be judged by pulse oximetry test alone.

Medications prescribed for IPF.

As we are experiencing controversy in the treatment of COVID, this is also true in the IPF cases. However, it is going on outside social media. Until recently, all new cases of IPF were prescribed prednisone, azathioprine and N-acetylcysteine. This protocol is now abandoned because of the lack of effectiveness.

What treatment modalities are helpful.

Oxygen therapy, in any and every way, to keep the oxygen saturation above 87 % at all times throughout 24 hours a day. Oxygen therapy delays the onset of Pulmonary hypertension and congestive heart failure. Lung transplantation, whenever possible, should be done. Lung transplant is considered curative therapy.

Are there any drugs to modify the immune response in IPF.

Several drugs are in the process of development. Two anti-fibrogenesis drugs have already been approved in order to slow down the formation of fibrous tissue. The results are encouraging but each one has significant side effects.

Names of Immunomodulators approved so far in the treatment of IPF.

Nintedanib (Ofev) is an oral medication given 3 times a day. It is a tyrosine kinase inhibitor. It slows down the progression of the disease mainly by stopping angiogenesis. Side effects are nausea, vomiting and anorexia. Early onset of drug resistance requiring discontinuation.

Pirfenidone (Esbriet). Given orally twice a day. The drug is an antifibrotic agent. Side effects include heartburn, nausea, diarrhea, anorexia and photosensitivity.

Is any Monoclonal Antibody drug available to treat IPF.

Pamrelumab, an anti-connective tissue growth factor (CTGF), has shown promise in the second stage of the trial. Several other monoclonal antibodies are in a development state.

Macrophage M2 antigen is isolated and currently, an antibody development against M2 is formulated.

What is the prognosis of IPF.

The disease is progressive and patients generally survive between 3 to 5 years from the time of the diagnosis.

The basic pathophysiology of IPF has gone through major revisions. The theory of inflammatory damage to the alveoli followed by fibrosis is no longer tenable. Inflammatory reactions, if any, in IPF are the result of damage of alveoli rather than the cause. The complex interactions between various cytokines, Leukotrienes, prostaglandins, immune cells and particularly the macrophage growth factor and platelet derived growth factor is complicated for easy understanding. IPF is a progressive and fatal disease and the treatment so far is not very satisfactory except for Lung Transplantation and continuous oxygen therapy.

***************************************************************

,

Mitochondrial Diseases

 

                                                      Mitochondrial Diseases

                                                   PKGhatak, MD

Mitochondrial diseases arise from the mutation of gene/genes in the DNA of mitochondria. Mitochondrial diseases are rare but fascinating to study, like solving a murder mystery.

What is the common link between all known mitochondrial diseases.

The abnormal gene is inherited solely from the mother. At the time of fertilization father's contribution is only one copy of chromosomes, and the mother gives the entire egg containing mitochondria, along with the other copy of the chromosomes.

One mitochondrion has 3,000 genes, and about 100 of these genes are involved in cellular respiration and energy production. The rest of the genes are responsible for all other cellular functions based on the tissues they are located in, for example, hormone production in endocrine organs, neurotransmitter production in nerve tissue, muscle contraction in the heart and other muscles, including the GI tract.

Any mitochondrial gene abnormality related to cellular respiration, so inherited, results in a deficiency in one out of 8 groups of cellular respiratory enzymes that are essential for releasing the potential energy of food in the form of heat and ATP (adenosine triphosphate). ATPs are used by the cells for carrying out all other cellular functions that are energy dependent.

The journal Science published an article on Mitochondria. Anyone interested in Mitochondrial disease must procure a copy and read the article. We know mitochondria originated in bacterial species, then migrated into human cells and have established a" microsymbiotic" relationship. Now it is revealed that mitochondria have a separate life span, " social structure", inter-mitochondrial communication channels, and by cytokines, and hormone-cortisone; and even help each other by touching each other, by developing microtubular arms, and by repairing defective DNA by donating healthy DNA through those microtubules. The authors have pieced together microphotographs into videos of the development of communicating arms. and their functions. The individual life span of mitochondria is not dependent on the life span of the resident cell. The article suggests that all metabolic diseases primarily arise from defective mitochondria. And this fact will revolutionize the medical treatment of Diabetes mellitus, autoimmune diseases, cancers and many other diseases.

In some instances, mitochondrial DNA gene mutations take place later in life. In most cases, the nuclear DNA gene mutations are responsible for Mitochondrial diseases.

The first mitochondrial disease was described by Dr. Robert Lust in 1951. In 1957, Dr. Archibald Denis Leigh demonstrated pathological lesions in the nervous system and located the abnormality in the mitochondria. At that time, to detect the cause of an inherited disease required painstaking tracing of illness among the family members, like contact tracing in the COVID pandemic. Nowadays, detection of gene mutation tests and blood and urine biochemical tests are easily available and cases are diagnosed early. In the coming years, more and more Mitochondrial diseases will be identified.

Understanding the symptoms of Mitochondrial diseases.

1. Energy generation and ATP synthesis.

We consume food that can be grouped into three categories. 1. Starch and sugars are called Carbohydrates. 2. Oil and fat are called fats. 3. Animal flesh and plant proteins as Proteins. After digestion, the carbohydrates end up as sugars, the fat as fatty acids, and the proteins as amino acids. Each one of these energy producing molecules becomes a Two-Carbon compound called Acetyl-CoA by the action of enzymes. The acetyl-CoA is then combined with a four-carbon molecule, oxaloacetate, to form a six-carbon compound, Citrate. That is the beginning of the tricarboxylic acid cycle or Krebs cycle.

Citrate, in turn,  becomes alpha glutamate in stages. Enzyme NADH (Nicotinamide Adenine Dinucleotide) dehydrogenase strips 2 electrons (Hydrogen atom) from alpha glutamate and transfers the electrons to NAD, a cofactor and H ion receptor, which now becomes NADH. The NADH, in turn, transfers the electrons to FAD (flavin adenine nucleotide) to become FADH by the enzyme succinyl dehydrogenase. In the next two stages, the electrons pass to Cytochrome C by the enzyme cytochrome C reductase, and the final stage by cytochrome C oxidase to one radical of oxygen to form one molecule of water and energy. The excess energy immediately mops up ADP (adenosine diphosphate) and the energy is stored in ATP, a high energy molecule.

Going back to the citric acid cycle, the alpha glutamate has turned into succinate, then to fumarate and then back to oxaloacetate, which is again ready to take another molecule of acetyl-CoA. These 8 steps, the citric acid cycle continues. All the stages in the citric acid cycle are reversible enzymatic actions. But the final stage of the electron transfer pathway is not reversible.

 

Biochemical basis of symptoms in mitochondrial diseases.

1. In mitochondrial disease, if a gene mutation happens in the tricarboxylic acid cycle or electron transfer cycle, then the newborns appear weak, lethargic and fail to thrive. In absence of oxidative reduction Lactic acid accumulates, patients will be acidotic and life will be hanging on a thread.

   2.  Distribution of Mitochondria. The metabolically highly active cells have more mitochondria than those tissues that are less active. However, Red Blood Cells (RBC) have no nucleus or mitochondria, even RBCs are highly active in transporting Oxygen. The eyelid muscle, eye movement muscles, heart, muscles of the throat, respiratory muscle, and nerve cells have more mitochondria and, as a result, exhibit early signs of the illness.

What are the common symptoms of the majority of mitochondrial diseases.

Poor growth in infants and children, failure to thrive in the newborn. Muscle weakness, drooping of the upper eyelids, and double vision from the weakness of the muscles of the eye. Deafness, heart failure, respiratory insufficiency, pneumonia, and frequent infections. Autism, various neuropsychiatric symptoms. Hypothyroidism, adrenal insufficiency, and Diabetes mellitus. Diarrhea, malabsorption. Lactic acidosis. 

 

Known Mitochondrial diseases.

Leigh syndrome, MELAS, Kean-Sayre syndrome, Mitochondrial deletion syndrome, Mitochondrial encephalopathy, Lactic acidosis, LHON syndrome, NARP syndrome, MANGIE syndrome.

Just by looking at the names, it becomes obvious when a rare case was first studied; they named the illness by the constellation of symptoms. Later, they added the name/names of the investigators to the syndromes. Much later, chemical tests and genetic mutations were established, and now that is the system of nomenclature.

Kean-Sayer Syndrome (KSS).

KSS is a neuromuscular disorder due to the mutation of mitochondrial genes. In some instances, deletion and duplication of genes are present. The deficiency of the enzyme-protein complex of the oxidative phosphorylation results in the failure of choroid plexus cells to transfer Folic acid to nerve cells of the CNS.

The onset of symptoms begins before the age of 20. The earliest symptom is ptosis, then ophthalmoplegia develops. One side of the body may be involved initially, and later, both sides are affected. Pigmentary retinopathy, cerebral ataxia, and deafness follow. Cardiac impulse conduction abnormality of the heart, growth hormone, and thyroid hormone deficiencies subsequently develop.

When biopsied tissue is stained with Gomori trichrome stain, the abnormal genes appear red, indicating a high ratio of abnormal genes compared with normal genes. The red colored genes are called Ragged Red Fibers (RRF). Finding RRF is considered diagnostic. Blood levels of lactate and pyruvate are elevated.

Treatment. Folinic acid, an active form of folic acid, is usually prescribed and improvement of symptoms occurs at least initially. Acidosis is treated in the usual manner.

MELAS syndrome. MELAS stands for encephalopathy, lactic acidosis, and stroke-like episodes. MELAS was first reported in 1984. The illness results from mutations in genes involved in the NADH dehydrogenase-protein complex.

Features of MELAS syndrome.

After normal early childhood development, the patients present with drooping eyelids. By the time patients reach 40 years of age, most patients have experienced transient but repeated episodes of profound weakness of one side of the body or the other side. Altered consciousness and seizures are often present. Migraine-like headache is an important feature. Late symptoms are lactic acidosis, loss of bowel control, labored breathing, ataxia, deafness, and muscle spasms.

In the early stage of the illness, Enzyme CoQ10, nicotinamide, riboflavin, and L- L-arginine are prescribed, and the results are variable.

Leigh syndrome.

The disease manifests in infancy.  The child fails to thrive. Diarrhea, vomiting, difficulty in swallowing, and seizures are the usual presentations. Examination reveals hypotonia, dystonia, wasting of muscles, paralysis of the muscles of the eyes, nystagmus, saccades, hypertrophic cardiomyopathy, and a Ventricular septal defect. A high forehead and large ears are distinct features. Peripheral neuropathy and Lactic acidosis follow. A more severe form of Leigh syndrome was reported from Quebec, Canada. The symptoms start in the newborn. The entire brain and liver are affected. Voluntary muscle weakness and atrophy dominate. Death usually happens at about 5 months of age. This subclass of Leigh syndrome is known as French Canadian Leigh syndrome.

In Leigh syndrome, in 80% of cases, genetic abnormalities are present in nuclear DNA genes, and 20 % in mitochondrial DNA. The defective genes are inherited in an autosomal recessive mode and also rarely by an autosomal dominant mode. The mutation of genes causes a deficiency of the cytochrome C dehydrogenase protein complex.

Other mitochondrial diseases mentioned above are still rare and are not highlighted here.

Mitochondrial diseases are not seen by practicing physicians unless they are specialists in Pediatric Neurology and Metabolism-Endocrinology. But this field is expanding due to the easier availability of gene analysis and understanding complex biochemistry. Many more obscure diseases will be rebranded as mitochondrial diseases in the future.

revised and edited: May 2025.

****************************************************

 

Memory and Dementia

  

                                                  Memory and Dementia

                                                PKGhatak, MD

What is memory.

Memory is the ability to recall previously learned somatic sensory, visual, auditory, taste and smell sensations, abstract ideas, dreams, subconscious experiences, and a combination of any of these, at an instance when required. Memories result from nerve cell reactivation, in specific areas of the brain, at various levels of activities, and the role of the interconnecting pathways to the neurons plays.

Location of memory centers in the Brain.

Hippocampus. Amygdala and Prefrontal Cortex are the chief memory centers.

Memories are three different kinds. 1. Short term memory. 2. Permanent memory and, 3. Working Memory.

Short term memory.

Memories are stored mainly in the Hippocampus and outlines of those experiences are also kept in the prefrontal cortex at the same time. The gradual consolidation of memory takes place in the prefrontal cortex and short term memory from the hippocampus disappears at the same rate. Others believe permanent memory develops at the same time the short time memory is developing in the hippocampus.

Permanent memory.

The prefrontal cortex, memory is known as the permanent memory.

Working memory.

The working memory is a complex short term memory where many other mental faculties work in harmony for the execution of a work plan. Example: driving an automobile to an address given to the driver over the telephone.

What is Dementia.

Dementia is defined as loss of memory, language, problem-solving and other thinking abilities that are severe enough to interfere with daily life.

Incidence of dementia in the USA.

The incidence of dementia among individuals aged 71 and older is about 14%. The incidence increases with increasing age.

Causes of Dementia.

The cause of dementia is due to the loss of function of memory cells due to disease or death.

Classification of Dementia.

The classification is based on the common link among the different entities. 

1. Progressive dementia. Dementia is not reversible.

Example: Alzheimer's disease, Lewy body dementia.

2. Vascular dementia. Damage to the blood vessels and to memory centers of the brain.

3. Frontotemporal dementia. Degeneration of the nerve cells in the frontotemporal cortex.

4. Mixed dementia.  Vascular dementia and progressive dementia often coexist.

5. Dementia as a part of other diseases. Examples. a) Huntington's disease

   b) Traumatic Brain Injuries (TBI). c) Creutzfeldt-Jakob disease. d) Parkinson's disease

6. Reversible dementia.

Subdural hematoma, normal pressure hydrocephalus, certain medications taken for various illnesses, like antihistamines, antidepressants. Alcoholism, Vitamin B1 and Vitamin B12 deficiency. Infections, Hypothyroidism, hypoglycemia, Lead poisoning, Hypoxemia, and brain tumors are some of the examples of reversible dementia.

7. Inherited and familial. Huntington's disease, Down syndrome. Alzheimer's disease.

Alzheimer's disease.

Alzheimer's disease (AD) is the most common dementia in the elderly population. AD is an irreversible and progressive disease. The onset of AD is insidious. The changes in the brain begin years before the first signs of dementia. Forgetfulness is the earliest symptom, slowly and steadily progressive loss of memory occurs, then progresses to loss of cognitive function, motor skills, logical thinking, social isolation and finally complete loss of activities of daily living develops.

Clinically AD is discussed under 1. Early,2. Moderately advanced and 3. Late stages based on the degree of disability

Basic biological changes are due to the accumulation of two abnormal proteins in the brain. Beta Amyloid protein -- due to an abnormal gene of an Amyloid Precursor Protein (APP) on chromosome 21. Apolipoprotein APOE 4 is produced instead of normal APOE protein. The abnormal beta amyloid protein accumulates between the microglia cells, astrocytes and neurons. The microglia cells, normally function as immunocytes of the brain and have phagocytic properties. They are unable to break down the beta amyloid. Accumulated beta amyloid forms plaques.  The connecting neuronal fibers and synapses gradually lose function and neurons die, the brain shrinks in size.

The second abnormal protein is Tau protein. TREM 2 gene encodes tau protein. This protein is present in the membrane receptors of microglia. The mutant TREM2 generated an abnormal tau protein - hyperphosphorylated, abnormally folded protein, which destroys the microtubules. Microtubules require ATP energy to transmit chemicals from one spot to the other within the cell. Hyperphosphorylations prevent microtubules from using ATP. Dying microglia release cytokines which further damage neurons.

Pathologically the loss of nerve fibers, synapses, and neurons is most noticeable in the hippocampus, cingulate gyrus, temporal lobes and parietal lobes.

Diagnosis of AD.

Diseased and damaged areas of the brain are detected by MRI, CT scan and Positron Emission Tomogram (PET) scan. A definitive diagnosis is made on brain tissue obtained by biopsy or at autopsy. Neurofibrillary triangles and a decrease in the number of neurons are demonstrated. Beta amyloid and tau proteins are identified by staining.

Treatment.

Based on the clinical stage of the disease management of AD varies. All aspects of medical therapeutics, physiotherapy, occupational therapy, behavior modifications, social integration and experimental treatment modalities are employed.

Therapeutics.

Two groups of drugs are used in the treatment of AD. 1. Acetylcholine esterase inhibitors. 2. N-Methyl D Aspartate Receptor Antagonists (NMDAR).

Acetylcholine esterase inhibitors. Acetylcholine is a neurotransmitter, in normal conditions, it is degraded from the synapses by the enzyme acetylcholine esterase. Increasing the local concentration of acetylcholine by blocking this enzyme shows some improvement of memory at least initially. The commonly prescribed drugs are Donepezil, Rivastigmine and Galantamine.

NMDAR. Glutamine is another neurotransmitter. But the excess accumulation of glutamine within the neuron is harmful to neurons. NMDAR blocks glutamine uptake by neurons. The approved drug is Memantine.

Prognosis. The prognosis of AD is poor. It is the 6^th common cause of death in the USA.

 Lewy Body Dementia (LBD)

Lewy body dementia is common in people over 50 years of age. An abnormal protein alpha synuclein accumulates in neurons of the brain. The neurons swell up with like a balloon due to accumulation of alpha synuclein. The neurotransmitters - Acetylcholine and Dopamine production are diminished.  Acetylcholine deficiency causes a decline in cognition, behavior change and alteration of sleep rhythm. Motor function abnormality and rigidity like Parkinson's disease develop due to dopamine deficiency.

Areas of the brain affected in LBD and consequences.

Neurons of the cerebral cortex – defective reception, thought and language difficulties.

The limbic area of the brain - emotion and behavior changes and fluctuations from time to time.

Hippocampus – difficulty in new memory formation.

Brain stem – sleep disturbance and fluctuating alertness.

Olfactory lobe – loss of smell sensation or abnormal sense perception.

Distinguishing features of LBD from other forms of dementia.

1. Fluctuating level of alertness. 2. Visual hallucination. 3. acting out dreams. 4. Gross impairment of abstract thinking and reasoning. 5. frequent episodes of delirium.

Risk factors.

Increasing age, presence of gene mutation of APOE e4, SNCA and GBA genes,

Treatment.

No specific medication is available for LBD. Symptomatic treatment is recommended. Prevention of falls and fractures of bones requires special attention. In most patients with various levels of assistance are required for activities of daily living.

Prognosis. It is not good. From the time of LBD diagnosis, most people die between 5 and 8 years.

Huntington's Disease (HD) and Dementia.

Huntington's disease is an autosomal dominant inherited disease. As the disease progresses,  the short term memory, permanent memory and work memory are all profoundly lost, leading to dementia.

HD results due to the accumulation of an abnormal protein - Mutant Huntingtin protein (mHTT) within the neuron in a wide area of the brain but the highest concentration is present in the Striatum. A moderate amount of accumulation of mHTT is present in caudate nuclei, putamen, hippocampus, Purkinje cells of the motor cortex, cerebellum, hypothalamus, and cerebral cortex.

The mHTT protein starts to accumulate in the cells. It is broken down by the enzyme Caspase. But the fragments quickly reform in a haphazard manner. This abnormally folded mHTT protein structurally resembles beta amyloid protein. The mHTT protein is present in both the nucleus and cytoplasm of the neurons and is known as inclusion bodies. The mHTT protein is toxic to the cells and results in cell death.

The mHTT protein deposition is also seen in the heart, testicles, liver, and lungs and produces symptoms from the damaged tissues of these organs.

Huntington's Disease is an autosomal dominant inheritance disease.  A mutation of a gene in the short arm of chromosome 4 is responsible for HD. The European population has more HD; the incidence is about 15 per 100,000 population. The symptoms of HD appear at ages 30 to 50 years of age. Less frequently, young adults in their 20s show signs of HD. Rigidity is the prominent symptom and features that resemble Parkinson's disease are present. In contrast to the older population, HD seizures are rare occurrences. But the disease progresses rapidly in the Juvenile form of HD.

Some special features of HD.   Seizures are not unusual; the presence of a characteristic eye movement is called saccadic eye movement. Muscle rigidity, incoordination, unstable gait resembles Parkinson's disease. Patients are emotionally labile. An increased rate of suicide is noted.

Diagnosis. Detection of abnormal chromosome 4 is essential. Siblings, children, and close relatives, even with no symptoms of HD, can have chromosome analysis done to detect their chance of HD if they wish and properly counseled.

Treatment. In general, medications are prescribed for the control of symptoms and complications that arise from HD. No cure is possible at present. Stem cell transplants are discussed but not performed.

For control chorea (abnormal purposeless dance-like movements) in HD, Tetrabenazine is approved.

Prognosis. For most patients, deaths usually take place in 15 to 20 years.

 

Dementia of Parkinson's disease (PD).

Parkinson's disease is a progressive, irreversible degenerative disease of the brain. Substantial nigra is primarily affected and results in a decrease in Dopamine production from the deaths of the neurons. About 2 % of people over 65 have Parkinson's disease.

Older PD patients with dementia suffer from repeated hallucinations and excessive daytime sleepiness.

Some special symptoms associated with dementia of Parkinson's disease.

Delusions and paranoid ideas are common, have difficulty in interpreting visual images, display conceptual memory loss, and react adversely to antipsychotic drugs, often lapsing into coma from their use.

Frontotemporal Dementia.

Of all the different causes of dementia, frontotemporal dementia has the most devastating impact on the patient and the family. Frontotemporal dementia appears at age 40, the incidence is equal in both sexes, has a strong family history and is inherited due to multiple genetic defects. The disease involves degeneration of neurons due to the accumulation of an abnormal protein, pink bodies in the neurons, involving many areas of the brain simultaneously, including the Limbic area and the Neocortex.

Features of frontotemporal dementia (FTD).

Abnormal behavior like stealing, swearing, excessive indulgence in sexual activities, apathy, language difficulties, halting speech, and carelessness about personal hygiene. Some develop poor muscle coordination, tremors, muscle spasms and swallowing difficulty. Hallucinations and delusions are present in others.

Classification of FTD.

Frontal variant where behavioral changes predominate. In Primary progressive aphasia- semantic dementia patients have great difficulties in understanding spoken words and initiating a conversation due to delayed speech. Degenerative diseases of the nervous system like Amyotrophic lateral sclerosis may also have this dementia.

Diagnosis of FTD.

The neuropsychological examination is the first step followed by an MRI or CT scan of the brain demonstrating multiple areas of involvement including the center of primitive functions in the Limbic area and behavior modification areas in the neocortex.

Treatment.

No treatment can change the basic defect in the brain, but symptomatic treatment can control some symptoms.

Vascular Dementia.

Vascular dementia develops due to diseases of cerebral blood vessels.

One major event, like strokes, may produce dementia or dementia follows from many mini strokes or vascular insufficiency. The symptoms of vascular dementia are variable based on the areas of the brain that are damaged. Dementia is a dominant symptom when the hippocampus and prefrontal area of the cortex of the brain bear the brunt of anoxia.

Predominant symptoms of vascular dementia are confusion, restlessness and agitation, poor attention span and mixed memory loss.

Risk factors include high blood pressure, cigarette smoking, drug use, diabetes mellitus, obesity and high blood cholesterol and triglycerides.

Treatment.

The main goal of therapy is to prevent further neurological episodes. Risk factors reduction, rehabilitation and symptomatic treatment.

Dementia associated with Traumatic Brain Injury.

Because of wide circulation in print media and electronic media regarding traumatic brain injury and its consequences, Traumatic brain injury (TBI) is a familiar subject. The attention of the public was drawn to this subject when Mohammad Ali, the famous heavyweight boxing legend, developed Parkinson's disease. More news soon followed detailing accounts of veterans struggling with this poorly understood entity at that time and also because of the news that many veterans committed suicide.

Professional players engaged in contact sports, college football players and others, who have sustained blows to the head resulting in concussion or unconsciousness or amnesia, later developed a symptom complex known as Chronic Traumatic Encephalopathy (CTE). Dementia is a part of the CTE symptoms.

Incidence. About 2 % of the adult population is known to have CTE. About 50% of CTE patients have a history of loss of consciousness.

Inheritance. The incidence of CTE is 10 times higher when the abnormal AOPE e4 gene is present. The mode of inheritance is not known, probably multiple gene mutations are possible.

Pathology. Beta amyloid protein, Tau protein, accumulation in the brain of 30 % CTE patients detected by autopsy examination. The most common areas of the brain showing abnormality are the hippocampus, amygdala, precuneus, parietal and frontal lobes of the brain.

Distinguishing features of CTE are headaches, sudden mood swings, explosive rage, drug abuse and suicide. Ataxia, dysarthria, rigidity and tremor are evident during examinations.

Treatment. Multidisciplinary medical therapies including psychological counseling are called for. The outcome of coordinated therapy is encouraging.

**********************************************************

AMYLOIDOSIS

 

                                                                       Amyloidosis

                                                                       PKGhatak, MD

Amyloidosis is not a single entity, under amyloidosis five distinct clinical disorders are included; whereas, 36 chemically distinct proteins associated with amyloidosis are detectable.

The underlying pathology is an accumulation of abnormal protein inside the cells. The abnormally folded protein is resistant to protease enzyme which in normal circumstances does "house cleaning" and it removes undesirable molecules from the inside of cells.

Organs involved in amyloid disease and clinical features.

Eyes.

The accumulated protein damages the cells and the cells die. Damage to blood vessels around the eyes produces easy bruising and the eyes resemble Raccoon eyes.

Amyloid in the retinal blood vessels reflects light back as bright spots. The retina appears as Starry Night when examined with an ophthalmoscope. Macular degeneration and various visual problems may develop.

 

 

 Heart

The cardiac muscles become loaded with amyloid and become stiff. The ventricles fail to dilate fully during diastole in order to accommodate returning blood. Stagnation of venous blood in the periphery and in the lungs produces congestive heart failure. Normal electrical conduction is disrupted and various heart blocks develop, and cardiac arrhythmia may appear.

Liver.

Accumulated protein results in enlarged liver, biliary obstruction and obstructive jaundice, elevated AST, ALT and Alkaline phosphatase in the blood are present

Mouth.

The enlarged tongue becomes out of proportion to the mouth cavity, the epiglottis enlarges. Obstructive sleep apnea follows.

Intestine. Diarrhea is a common presentation, malabsorption and weight loss follow.

Kidneys.

Damaged glomeruli result in high Creatinine and BUN and later renal failure develops. Loss of protein in the urine produces nephritic syndrome.

Peripheral Nervous System.

Neurological manifestations include peripheral nephropathy of both somatic and autonomic nervous systems and produce various clinical pictures including carpal tunnel syndrome, peripheral neuritis, and orthostatic hypotension.

The spleen is generally spared, but when it occurs it produces Howell-Jolly bodies in RBCs.

Skin.

Spotty depigmentation of skin with surrounding hyperpigmented areas in the lower legs is seen.

Endocrine organs.

The thyroid gland and adrenal glands may be involved in producing hypothyroidism and adrenal insufficiency respectively. Pancreas gland amyloid may cause diabetes mellitus.

Joints.

Joint amyloidosis is seen in patients undergoing hemodialysis for a long time. Beta 2 macroglobulin is deposited in knees, wrists, elbows and hips joints.

Clinical classification.

The old classification is Primary and Secondary amyloidosis. The cause of primary amyloidosis is unknown. In the secondary category, amyloid accumulation is the result of the chronic inflammatory process.

Current classification.

1. AL amyloidosis is also called Primary amyloidosis. The immunoglobulin light chain accumulates in the cells of the heart, kidney, liver and peripheral nerves.

2. AA amyloidosis is also called Secondary amyloidosis. An acute phase protein is deposited in cells with chronic inflammation, like Rheumatoid arthritis and other illnesses. Involved organs are the kidneys, liver, and spleen.

3. Hereditary or Familial amyloidosis. Due to an inherited defect of the liver enzyme. The liver cells make an abnormal protein called Transthyretin (TTR). TTR accumulates in liver cells, the Heart, kidney, and peripheral nervous system. Various symptoms are seen depending on the organ impacted.
   

4. Wild Type amyloidosis. Here the TTR protein accumulates in the heart of people over 70 years of age. Rarely carpal tunnel syndrome is seen.

       But in the wild type, the disease is not inherited. The cause is unknown.

5. Localized amyloidosis. Here the accumulated protein appears in an isolated organ. Urinary bladder, skin, throat and lungs are involved.

Diagnosis of Amyloidosis.

Biopsy of abdominal subcutaneous fat and staining tissue by Congo red is the final diagnostic method. If fatty tissue Congo red is negative, then a biopsy of the involved organ is indicated.

Blood test. Serum protein electrophoresis detects the offending protein-free immunoglobulin light chain.

Evaluation of the cardiovascular system by echocardiogram, conduction study and Troponin I, NT-proBNP and BNP may also be used but not diagnostic, but a cardiac muscle biopsy is diagnostic.

Treatment of Amyloidosis.

The treatment of amyloidosis varies according to clinical types.

For AL amyloidosis, Stem Cell Transplantation is the best option, however, only about 20% of patients become eligible for stem cell transplants. The rest of this group is generally prescribed Melphalan, Cyclophosphamide, and Dexamethasone.

In AA amyloidosis, Eprodisate (Kiacta) is most effective.

Patients with ATTR (hereditary) amyloidosis have the best outcome following liver transplantation.

The FDA has approved a new drug,  Amuttra. for the treatment of hereditary amyloidosis. This medicine blocks Trasethytrin production.

Prognosis.

ATTR amyloidosis patients have the best prognosis; 10-year survival is not unusual.

The patients in other groups have a poor prognosis, generally 2 to 3 years.

Symptomatic treatment for congestive failure, heart block, etc., is used in the usual manner.

 edited May 2025.

***************************************************