Amyloidosis (I)

choi

Lisa Sanders, Out of Breath. When the man began coughing up blood, it seemed his lungs were the most obvious place to look for a cause. But obvious isn't always right. New York Times Magazine, Aug 1, 2021.
https://www.nytimes.com/2021/07/ ... osis-diagnosis.html
https://hotlifestyletale.com/ent ... but-his-lungs-looke

Note:
(a) "They were near an urgent-care center in Brewster, NY. * * * his oxygen level was at 91 percent. Even with the worst cold, his oxygen should have been 98 to 100 percent. Did he feel short of breath? Not particularly, he said. Maybe when he was walking from the car, but sitting here now? Not at all. He needed a CT scan of his chest, the couple was told, and so he was transferred to the emergency department at Northern Westchester Hospital [1916- ; private] in Mount Kisco, NY."
(i)
(A) What is Urgent Care and When Should You Use It?, Icahn school of Medicine at Mount Sinai, undated
https://www.mountsinai.org/locat ... what-is-urgent-care
("Life-threatening emergencies, such as a heart attack or serious head injury, require a visit to the emergency department, also called the emergency room (ER). An illness or injury that does not appear to be life threatening but can’t wait until the next day should be treated at an urgent care center.  Urgent care centers provide easy access to quality healthcare for the times when your primary care physician’s offices are closed.")
(B)  An independent medical school and not part of a university, Icahn School of Medicine at Mount Sinai (ISMMS) was chartered in 1963 by Mount Sinai Hospital (both school and hospital are private; Founded in 1852 by Jews who felt they were discriminated against as patients and physicians in 1852, hospital opened in 1855). Classes began in 1968. Each year, the school matriculates 140 MD students. Each year about 25 MD/PhD students ("time to degree: 7.8 years": school website) are accepted, but I do ot know whether these are part of the 140 or outside.   
(ii) Brewster, New York
https://en.wikipedia.org/wiki/Brewster,_New_York
(a village)
(iii) Hypoxia. Mayo Clinic, undated
https://www.mayoclinic.org/sympt ... nition/sym-20050930

two consecutive paragraph:

"Hypoxemia is determined by measuring the oxygen level in a blood sample taken from an artery (arterial blood gas). It can also be estimated by measuring the oxygen saturation of your blood using a pulse oximeter — a small device that clips to your finger.

"Normal arterial oxygen is approximately 75 to 100 millimeters of mercury (mm Hg). Values under 60 mm Hg usually indicate the need for supplemental oxygen. Normal pulse oximeter readings usually range from 95 to 100 percent. Values under 90 percent are considered low.

(iv) "Did he feel short of breath? Not particularly, he said. Maybe when he was walking from the car, but sitting here now? Not at all. Not particularly, he said. Maybe when he was walking from the car, but sitting here now? Not at all."
(A) "Did he feel short of breath?" was a question posed by the nurse.
(B) I was stumped by this sentence: "Maybe when he was walking from the car, but sitting here now?"  I thought this also came from the nurse and did not think it (sentence) was right. But Americans said this sentence came from the patient, with the question omitted.
(v) Mount Kisco, New York
https://en.wikipedia.org/wiki/Mount_Kisco,_New_York  
("is a village and town in Westchester County, New York, United States. The town of Mount Kisco is coterminous with the village. The population was 10,877 at the 2010 census")


(b) "pulmonary embolus, which could have caused his low oxygen and hemoptysis (coughing up blood) without other symptoms. Even so, the images were far from normal. There were patches of a light haze in areas that should be dark in both lungs. Maybe pneumonia? People usually feel sicker than this man when they have pneumonia [my observation: pneumonia makes a patient look very sick, and the patient feels very sick also]"
(i) Vrinda Vyas and Amandeep Goyal, Acute Pulmonary Embolism. StatPearls, updated Aug 10, 2020
https://www.ncbi.nlm.nih.gov/books/NBK560551/
("After coronary artery disease and stroke, acute pulmonary embolism is the third most common type of cardiovascular disease. * * * Pulmonary emboli are typically multiple [obstructing various sites of lungs], with the lower lobes being involved more frequently than the upper, and bilateral lung involvement being more common. * * * PE leads to impaired gas exchange due to obstruction of the pulmonary vascular bed leading to a mismatch in the ventilation to perfusion ratio because alveolar ventilation remains the same * * *

At Northern Westchester Hospital: "Dr Tara Shapiro was the doctor assigned to his care
(i) Tara E Shapiro, DO.  Montefiore Medical Center, undated
https://www.montefiore.org/body. ... etail&ref=20887
("Department                Family Medicine
Practice Specialty                Hospice & Palliative Medicine
Medical Education                NY College of Osteopathic Medicine
Residency                Long Island Jewish Med Ctr - New Hyde Park
Fellowship                Jamaica Medical Center
Main Location                Montefiore Medical Center")

She graduated in 1993 from College of Osteopathic Medicine (COM), New York Institute of Technology (NYIT). The private NYIM was formed in 1955 with main campus on Manhattan. Its COM was established in 1977 and based in Village of Old Westbury, Long Island (western border of Old Westbury is separated by four miles from eastern border of Borough of Queens, New York City.
(A) The Irish female given name Tara is from Hill of Tara.
https://en.wikipedia.org/wiki/Hill_of_Tara
(B) The Jewish (eastern Ashkenazic) surname Shapiro means a person "from the Yiddish name of the German city of Speyer." Dictionary of American Family Names, by Oxford University Press.
(ii) Montefiore Medical Center
https://en.wikipedia.org/wiki/Montefiore_Medical_Center  
(1884- ; set up by Jews to honor Sir Moses Montefiore; the primary teaching hospital of the Albert Einstein College of Medicine)
Established in 1953 and located in the Bronx, Albert Einstein College of Medicine used to be part of Yeshiva University. Due to medical school's perennial financial loss, the university transferred in 2015 the control (but not ownership) to Montefiore.
(A) Montefiore
https://en.wikipedia.org/wiki/Montefiore  
(a Sephardic surname; "Meaning 'flower mountain,' its Ashkenazi equivalent would be 'Blumberg' or 'Bloomberg' ")  

Originally it was an Italian surname, so in Italy the last e is pronounced. I do not know whether the surname's pronunciation is Americanized in US, by dropping the last e.
(B) German-English dictionary:
* Blume (noun feminine): "flower"
https://en.wiktionary.org/wiki/Blume  
(C) Italian-English dictionary:
* fiore (noun masculine): "flower"
https://en.wiktionary.org/wiki/fiore
(D) Spanish-English dictionary:
* flor (noun feminine): "flower"
https://en.wiktionary.org/wiki/flor
  
(iii)
(A) The English noun hemoptysis (accent on the second syllable; the p is pronounced in both Merriam-Webster.com and Lexico.com.
(B) Jacob L Bidwell MD and Robert W Pachner, MD (both of Univ of Wisconsin medical school), Hemoptysis: Diagnosis and Management. Am Fam Physician (full name of the journal: American Family Physician; published by American Academy of Family Physicians (AAFP) ), 72: 1253 (2005)
https://www.aafp.org/afp/2005/1001/p1253.html

Quote (all footnotes omitted):

"Hemoptysis is defined as the spitting of blood derived from the lungs or bronchial tubes as a result of pulmonary or bronchial hemorrhage. Hemoptysis is classified as nonmassive or massive based on the volume of blood loss; however, there are no uniform definitions for these categories. In this article, hemoptysis is considered nonmassive if blood loss is less than 200 mL per day. The lungs receive blood from the pulmonary [which is venous] and bronchial arterial systems. The low-pressure pulmonary system tends to produce small-volume hemoptysis, whereas bleeding from the bronchial system, which is at systemic pressure, tends to be profuse. Blood loss volume is more useful in directing management than in reaching a diagnosis.

"Infection is the most common cause of hemoptysis, accounting for 60 to 70 percent of cases.5 Infection causes superficial mucosal inflammation and edema that can lead to the rupture of the superficial blood vessels.

"Primary lung cancers account for 23 percent of cases of hemoptysis in the United States.

"Cardiovascular conditions that result in pulmonary venous hypertension can cause cardiac hemoptysis. The most common of these is left ventricular systolic heart failure.

(C) Our patient had chronic heart failure in both right and left ventricles. Failure of right ventricle causes blood to back up in the body (bringing about edema and/ or ascites) except lung, so both lungs will be clear. Failure of left ventricle caused blood to to back up in both lungs, causing
• patches of haziness, due to exudates (leakage from pulmonary artery and its branches (which carry venous blood) in the lungs,
• pleural effusion (water in between pleural membrane and chest wall),
• or both.  
(D) "bronchial arterial systems"

The lungs need its own (arterial) blood supply to confer both oxygen and nutrients. Bronchial arteries usually come directly from descending aorta.
  


(c) "Ronald Wallach * * * It was the EKG done in the emergency department that provided Wallach with the last clue he needed to make his diagnosis. An EKG measures the electricity generated by the heart in order to make the muscles contract effectively. A thick, muscular heart will make an EKG tracing that is bigger, more exaggerated than normal. The more muscle present, the bigger the signal. But this man's heart generated a signal that was smaller than normal. Less electricity could suggest less muscle. Was this man's heart enlarged by something other than muscle? * * * A cardiac MRI"
(i) Ronald Wallach, MD (from Columbia with residency in its teaching hospital New York Presbyterian Hospital), FACC (Fellow of the American College of Cardiology) is certified by American Board of Internal Medicine (ABIM) in Cardiovascular Disease. He practices exclusively at Mount Kisco Medical Group (not Northern Westchester Hospital).
(ii) ECG or electrocardiography
https://en.wikipedia.org/wiki/Electrocardiography  
measures the vector (direction and strength) of electricity propagation in heat muscle. A standard ECG has 12 leads. Each lead is composed of a negative and a positive. If an electricity vector moves from negative to positive, it will be recorded as a "^." On the other hand, if the vector moves the other direction (from negative to positive), it will be recorded as a "v."

An atrium has little muscle, and thus no hypertrophy. In case of ventricular hypertrophy (heart muscle cells are constant in number but increases in size), a vector is bigger: ^ becomes taller (and duration might be a bit longer).  

In amyloidosis of heart, a vector is weakened (due to presence of impurity: amyloid fibrils) and the corresponding ECG recording is more subdued (shallower).
(iii) Oda S et al, Trends in Diagnostic Imaging of Cardiac Amyloidosis: Emerging Knowledge and Concepts. RadioGraphics (published by Radiological Society of North America (RSNA) ), 40: 961 (2020)
https://pubs.rsna.org/doi/full/10.1148/rg.2020190069
("Although advanced CA can be detected easily at cardiac MRI, early cardiac involvement is more difficult to detect, and the distinction of CA from other phenocopies is challenging")

(d) "Cardiac amyloidosis can be a result of a cancer known as multiple myeloma. In this cancer, a type of white cell called a plasma cell creates abnormal fibers that can break down and form the characteristic saw-toothed fibers of amyloidosis. These jagged fibers can also be a result of aging. In this version of the disease, carrier proteins known as transthyretins break down and take on the abnormal but characteristic irregular folds of amyloidosis. In both diseases, these serrated fibers travel through the body, invading and accumulating in muscle [actually in multiple organs; not just muscles] — often the heart muscle. Tests on blood and urine quickly showed that his disease wasn't due to myeloma. * * * A biopsy of the heart muscle proved that it was the form of amyloidosis associated with aging. This type of amyloidosis is also progressive but much more slowly."
(i) A descendant of B lymphocytes, plasma cells produce antibodies. A clone of plasma cells produces antibodies against identical antigen. When that clone becomes malignant, the disease of multiple myeloma develops; the monoclonal antibody permeates the body, some of which are excreted via kidney in urine (in the forms of light chain dimers without heavy chains; an antibody is made up of both light and heavy chains), called Bence Jones protein. English physician Henry Bence Jones (father Jones and mother maiden name Bence) described the phenomenon in 1847.
(ii) Myocardial Biopsy.
https://medlineplus.gov/ency/article/003873.htm
("through a catheter [inserted from a vein] that is threaded into your heart (cardiac catheterization)" )
(iii) "amyloidosis associated with aging"
(A) The diagnosis is ATTR-CM, which stands for
transthyretin (TTR) amyloidosis, cardiomyopathy, which is quite common (except that most people are not affected by it).
(B) ATTR is systemic (deposition of deformed or misfolded transthyretin throughout the body), but its involvement with heart muscle stands out. There is no medication for this disease.
(C) transthyretin
https://en.wikipedia.org/wiki/Transthyretin
("carries the thyroid hormone thyroxine (T4) and retinol-binding protein bound to retinol")

Retinol is also known as vitamin A.

Transthyretin and retinol-binding protein are two separate proteins in serum. Some say transthyretin "complexes" (meaning: associates) with -- rather than carry -- the retinol-binding protein.


(e) "I asked Wallach how he could make this diagnosis when other doctors had not. He called it the Aunt Tilly Sign."
(i) Aunt Tilly. Disney Wiki, undated
https://disney.fandom.com/wiki/Aunt_Tilly
("Aunt Matilda 'Tilly' is a character who appears in the Disney Junior animated series Sofia the First, voiced by Bonnie Hunt. She is Sofia's whimsical and adventurous step-aunt and King Roland's older sister who is a Duchess and a brave adventurer")
(ii) Sofia the First
https://en.wikipedia.org/wiki/Sofia_the_First
(section 2 Plot; section 4 Episodes)

This Wiki page does not mention Matilda or Tilly.
(iii) Matilda (name)
https://en.wikipedia.org/wiki/Matilda_(name)


--------------------text
“I’ve been coughing up blood,” the 59-year-old man confessed to his wife as they drove toward New York City from their home in Connecticut. It started the night before, he admitted when she asked. After 40 years of marriage, his wife, a nurse, was used to this kind of nonchalance from her husband, though it always carried a kind of punch. Take this exit, she instructed. They were near an urgent-care center in Brewster, N.Y. He needed to get this checked out.

It was quiet when the couple walked in to urgent care, so her husband was seen right away. He had a runny nose and a cough for the past couple of days, and a few times he’d seen streaks of blood in what he coughed up, he told the nurse. His chest hurt a little when he took a deep breath, but otherwise he felt just fine. His vital signs, however, told a different story. He didn’t have a fever, but his oxygen level was at 91 percent. Even with the worst cold, his oxygen should have been 98 to 100 percent. Did he feel short of breath? Not particularly, he said. Maybe when he was walking from the car, but sitting here now? Not at all. He needed a CT scan of his chest, the couple was told, and so he was transferred to the emergency department at Northern Westchester Hospital in Mount Kisco, N.Y.

The CT didn’t reveal any clots in the arteries of the lungs, so he didn’t have the feared pulmonary embolus, which could have caused his low oxygen and hemoptysis (coughing up blood) without other symptoms. Even so, the images were far from normal. There were patches of a light haze in areas that should be dark in both lungs. Maybe pneumonia? People usually feel sicker than this man when they have pneumonia, but how else could they explain the low oxygen level? He was started on antibiotics and admitted for observation.

Crisis in the Harbor

Dr. Tara Shapiro was the doctor assigned to his care that night. She was not at all sure the problem was in the man’s lungs. The CT scan also revealed a heart that was thicker and more muscular-looking than it should be. This kind of hypertrophy, as it’s called, is frequently seen in patients who have high blood pressure, when the heart has to work hard to squeeze its payload into the bloodstream. But this man didn’t have high blood pressure.

The patient had a full cardiac work-up a few months earlier that he said was normal. But Shapiro was still worried that it was his heart and not his lungs that was failing him. His oxygen level improved greatly in just the few hours he’d been in the hospital. It was far too early for the antibiotics to have done this. More likely it was from the powerful diuretic he’d already been given in case the haziness in his lungs was fluid rather than an infection. A muscular heart doesn’t pump as well as a normal heart and sometimes can’t keep up. When that happens, fluid can get backed up — right into the lungs.

Shapiro reached out to a cardiologist colleague, Dr. Ronald Wallach. He was one of the most knowledgeable doctors she knew. Wallach saw the patient the following day, just before he was discharged. The patient’s wife was reassured by the doctor’s white hair and air of quiet authority. Her husband, something of a hardhead, would certainly listen to this guy.

After hearing the man’s story, Wallach asked if he had been short of breath before. Well, maybe it had been going on for a while, the man acknowledged. How long? The man’s wife gave him a sharp look. Certainly for the past several months, at least since the summer, he said. That’s when he’d had some serious trouble breathing.

He was out one weekend on his motorboat with his wife and adult daughter. The women were on inner tubes in the cove just behind New Rochelle Harbor, enjoying the sun and calm waters. Then suddenly: “Throw me the rope,” he heard his wife shout. He looked up to see the two women moving rapidly away from his boat, caught in the oceanbound tide. He wrapped one end of a rope around his body and threw the other end out to his wife. It took a couple of tries, but she got it. He struggled to pull wife and daughter back to the side of the boat. As they clambered over the side, it was his wife who noticed his breathing. His face was red and shiny with sweat, and he was panting for breath. Are you OK? she asked. He nodded his head and held up a finger as if to say give me a minute. It took more than a minute — a lot more. It scared her. He was a tough guy, but it might have scared him too, because, though he refused to go to the emergency room then, he did see his primary-care doctor later that week.

That doctor immediately sent him to a pulmonologist and then a cardiologist. The lung doctor gave him a diagnosis of asthma. It’s unusual at this age, the doctor said, but it happens. He gave the patient an inhaler to use when he felt short of breath. It didn’t help. The cardiologist ordered a stress test. The patient lasted only a few minutes before he was too out of breath to continue. His EKG was normal throughout the test, so his cardiologist chalked it up to his asthma. He was an elevator mechanic and that meant that most days he had to climb stairs — sometimes lots of stairs — to fix broken machinery. The man noticed the stairs had become a little harder on him over the past year or so, but, he asked Wallach with shrug and a smile, what can you do?

Zigzag Fibers

It was the EKG done in the emergency department that provided Wallach with the last clue he needed to make his diagnosis. An EKG measures the electricity generated by the heart in order to make the muscles contract effectively. A thick, muscular heart will make an EKG tracing that is bigger, more exaggerated than normal. The more muscle present, the bigger the signal. But this man’s heart generated a signal that was smaller than normal. Less electricity could suggest less muscle. Was this man’s heart enlarged by something other than muscle?

There are diseases that can invade cardiac muscles to make them look bigger but be weaker. A disease like that could account for all the man’s symptoms — the thick-looking walls, the overflow into the lungs, the strange EKG, the shortness of breath, even the hemoptysis. “I think you might have something serious,” Wallach told the patient. A cardiac M.R.I. could give them the answer. The patient got that test a few days later. He wasn’t out of the scanner for more than 20 minutes when his phone rang. It was Wallach. The images told the story: The man had a disease known as amyloidosis.

Amyloidosis is the final result of many disease processes that ultimately cause zigzag-shaped fibers to accumulate in different parts of the body. Cardiac amyloidosis can be a result of a cancer known as multiple myeloma. In this cancer, a type of white cell called a plasma cell creates abnormal fibers that can break down and form the characteristic saw-toothed fibers of amyloidosis. These jagged fibers can also be a result of aging. In this version of the disease, carrier proteins known as transthyretins break down and take on the abnormal but characteristic irregular folds of amyloidosis. In both diseases, these serrated fibers travel through the body, invading and accumulating in muscle — often the heart muscle.

Tests on blood and urine quickly showed that his disease wasn’t due to myeloma. That was a relief; the prognosis for patients with cardiac amyloidosis from multiple myeloma is poor. They often die within a year of getting the diagnosis. A biopsy of the heart muscle proved that it was the form of amyloidosis associated with aging. This type of amyloidosis is also progressive but much more slowly. The patient was referred to a cardiothoracic surgeon at Columbia University. Sooner or later, he was going to need a heart transplant.

Three years passed before Wallach heard again from the patient. He wrote to let Wallach know he’d received his heart transplant and was doing well. He was writing to say thank you: “You saved my life.”

I asked Wallach how he could make this diagnosis when other doctors had not. He called it the Aunt Tilly Sign. “If I described Aunt Tilly to you and sent you out into a crowd to find her, you’d probably fail. But if you’d ever seen Aunt Tilly” — he snapped his fingers — “no problem. You’d find her in a second. It’s all about recognition.”