Fundamentals 2: 11:00am-12:00pm Scribe: Susanna Pischek 1

Tuesday, October 20, 2009 Proof: Matthew Davis

Dr. Ken Waites This session is from the Interactive Pathology Lab’s website. Go to: http://peir.path.uab.edu/iplab. When you get there, go to lab 6: Immunopathology. Dr. Ken Waites will lead the discussion on the material.

The way we are going to do Case Studies as part of the pathology component is with laboratories that are all Internet based. These are designed to provide a complement to the lecture. For example, when you are talking about a disease and a patient with the disease, to show you what manifestations of the disease there were, the cause of the disease, how the things that went wrong produce the disease and the facts that you’re learning, we will be using case studies. These case studies are used as complement and you are to learn them on your own. This works very well whenever it is convenient for you (here at school or at home). These are designed as self-instructional activities. I will spend time with you on each case study because you will need to know how to read these and recognize things to get what you need out of the case studies. The syllabus has the web address to access the case studies. There are a total of 13 different laboratories each one having case studies in them. The neoplasia is taught later in your immunology course. We are going to skip down to immunopathology, diseases of the immune system. We’re not going to spend a great deal of time on each one of them, but the way they are organized is that if the patient dies, the autopsy is given or if not a fatal case, the results are described. These study questions should be done on your own because this will let you be able to describe things. Being able to observe something, whether it is a lesion, using the correct terminology. These are terms that you should know and you can click on them for more information. If you don’t think there is enough information on the disease, you can click on the links that provide extra information. This is a very nice resource if you’re studying. These diseases that you will be studying were discussed in the lectures. We will start with Rheumatoid Arthritis.

Rheumatoid Arthritis

It is an autoimmune disease of the joints, where you have antibodies that have produced against your own tissue. The tissue begins to swell, get red, get hot, and to eventually become very damaged. This particular case is a 57-year-old white female had suffered from rheumatoid arthritis for 20 years. She’s developed many pathological issues within her body as a result of this disease. During this period, many joints were involved, some seriously. Because of the severe pain of this arthritis the patient was placed on steroids and was given analgesics, some of which contained acetaminophen (Tylenol). The patient also took additional analgesics (aspirin and/or acetaminophen) to help control the pain. The patient was admitted to the emergency room for weakness and hematemesis. On admission the patient's hematocrit was 21% (click on word and see what the normal value should be; in this case 34-44%). Why do you think she had that? She took aspirin and steroids. Both of those drugs plus the drugs she was taking for the diseases can cause ulcers and bleeding. Endoscopy demonstrated a large bleeding Fundamentals 2: 11:00am-12:00pm Scribe: Susanna Pischek 2

Tuesday, October 20, 2009 Proof: Matthew Davis

Dr. Ken Waites ulcer and fresh blood in the stomach and proximal duodenum. The sites of bleeding were cauterized; however, shortly after the procedure the patient became hypotensive and died despite aggressive resuscitation.

What were the Autopsy Findings?

There were numerous erosions and ulcers in the gastrointestinal tract and a large quantity of fresh blood in the gastrointestinal tract. There was also significant swelling and deformation in multiple joints. On the medial aspect of the right foot there was a firm, irregular, rubbery subcutaneous nodule measuring 2 x 1.5 cm. The cut surface was whitish-yellow and fibrous.

What are the abnormalities? (First image) The hands tend to flex toward the ulnar bone. You can see the hands are grossly misshapen. (Second image) If you look microscopically, the joint capsule surrounding the metacarpal joints are surrounded by lymphocytes. Note the thickening of the capsule and the focal accumulation of inflammatory cells surrounding a central area of fibrinoid necrosis (arrow). (Fourth image) This is a gross photograph of the foot from this same patient. Note the subcutaneous nodule on the medial aspect of the foot (arrow). These nodules can occur all over the body, usually on the affects the hands and prevents the ability of manual dexterity.

Rheumatoid factor that is IgM antibody directed against IgG.

Thyroid: Graves' Disease

This 18-year-old girl presented with complaints of swelling in the neck, weight loss, bulging of the eyes (aka “bug eyed”), tremor, decreased heat tolerance, loose stools, and occasional palpitations. Physical examination revealed normal blood pressure, resting tachycardia of 110 beats per minute, mild exophthalmos, eyelid lag, and a diffusely enlarged thyroid gland. Pertinent laboratory findings were thyroxine (T4) level 30.8 mcg/dL, free thyroxine was 2.7 ng/dL, and thyroid stimulating hormone (TSH) was 0.22 mcIU/mL. She was given propylthiouracil until she became nearly euthyroid, at which time a thyroidectomy was done.

Autopsy Findings

The thyroid gland weighed 45 grams (average weight 25g). It was beefy red in color and had a homogeneous fleshy consistency.

The audio cuts out; however, Dr. Waites goes through the images and reads their descriptions. He reminds us that hematemesis is the vomiting of blood and that an enlargement of thyroid is referred to as a goiter.

Thyroid: Hashimoto's Thyroiditis Fundamentals 2: 11:00am-12:00pm Scribe: Susanna Pischek 3

Tuesday, October 20, 2009 Proof: Matthew Davis

Dr. Ken Waites This was a 49-year-old woman who complained during her yearly physical examination of tiredness and difficulty concentrating. She attributed these symptoms to stress at work. She had gained weight over the last year and despite warm weather, she felt chilled without a sweater. Family history was significant for hypothyroidism in her mother and older sister. On physical examination she had a pulse of 58 bpm and a blood pressure of 138/88 mm Hg. Examination of her neck disclosed a small thyroid gland with a palpable pyramidal lobe and a firm, bosselated texture. Serum taken at this time demonstrated a total T4 of 7.0 mcg/dL and a TSH of 22.0 mcIU/ml. In addition, antithyroglobulin antibodies were positive at 1:640 and antimicrosomal antibodies were positive at 1:5120. These results supported the clinical impression of hypothyroidism; also, the texture of her thyroid gland and a positive family history suggested an autoimmune etiological factor. She was referred to an endocrinologist for further evaluation; however, before beginning treatment she died suddenly from a ruptured berry aneurysm of the middle cerebral artery.

Autopsy Findings

At autopsy, significant subarachnoid hemorrhage from the ruptured berry aneurysm was documented. In addition, the thyroid gland was mildly enlarged and firm. On cut section the tissue was slightly pale.

Dr. Waites describes the images and states that lots of blue coloration is indicative of the presence of lymphocytes. Think lymphocytosis when you see a lot of purple/blue dots (as seen in images 3, 5 and 7 that Dr. Waites pointed out).

Polyarteritis Nodosa

This was a 27-year-old white female who presented to the emergency room with fever, diarrhea, and abdominal pain that had increased in intensity over a 3-day period. Many autoimmune diseases that we’re studying tend to affect women more than men. Her blood pressure on admission was 165/108 mm Hg. She had been diagnosed with polyarteritis nodosa two years prior to this admission and had been treated with corticosteroids and cyclophosphamide. She had discontinued her corticosteroids because they made her gain weight; in addition, she was not taking the medications prescribed for her hypertension. At this admission it was suspected that the patient had bowel ischemia due to mesenteric artery occlusion. Angiographic evaluation revealed significant vascular damage to the mesenteric arteries with aneurysmal dilatations and thromboses. Significant vascular changes were also observed in the renal and hepatic circulation. On the second hospital day, the patient developed acute severe abdominal pain and an emergency laparotomy was performed to resect an 18-cm section of infarcted and ruptured ileum. After surgery she continued to run a Fundamentals 2: 11:00am-12:00pm Scribe: Susanna Pischek 4

Tuesday, October 20, 2009 Proof: Matthew Davis

Dr. Ken Waites fever, her white blood cell count was 13,500 cells/cmm, and she developed renal failure. Two days after surgery the patient died due to sepsis and multisystem failure.

Autopsy Findings

At autopsy there were several 0.5 to 1.0-cm firm nodules in the dermis. There were numerous aneurysmal dilatations grossly visible in the mesenteric arteries. There were multiple shrunken infarcts on the surface of the kidneys and the surface also had a fine granular appearance indicative of hypertensive renal disease. On cut section both the kidney and the liver had multiple firm white nodules.

Image 1 depicts an angiogram of the abdominal viscera demonstrating numerous aneurysms throughout the mesenteric circulation. Note the microphotos of the mesenteric vessels in the following images.

Lung: Scleroderma

This 29-year-old black female had a history of scleroderma involving the lung, kidney, heart, and skin. Her main clinical problems centered on her restrictive lung disease. She was able to live at home with supplemental oxygen but recently she had developed edema, chest pain, weakness, light-headedness, and a loss of appetite. The patient was admitted to the hospital with a working diagnosis of congestive heart failure brought on by her lung disease. Echocardiographic evaluation revealed a pericardial effusion that was tapped. Soon after this procedure her respiratory status degenerated and she required intubation. Despite aggressive supportive treatment for her cardiac and pulmonary problems, she could not be weaned from the ventilator. Two weeks after admission she became febrile and Gram positive cocci were isolated from sputum culture. She was placed on antibiotics but her condition deteriorated and she developed bradycardia followed by electromechanical dissociation (EMD).

Autopsy Findings

Upon opening the thorax there was 600 cc of cloudy serous fluid in each hemithorax and 100 cc of similar fluid in the pericardial sac. The heart weighed 530 grams and there was thickening of both the left and right ventricular walls. The liver weighed 1880 grams and was congested. The spleen weighed 200 grams and was also congested. The combined lung weight was 1875 grams; the lungs were markedly fibrotic with severe emphysema. In addition, dermal thickening was evident throughout the body and the wall of the esophagus was thickened and firm.

Dr. Waites explained on image 5 (gross photograph of the heart from this case) that there is thickening of the left ventricular wall and some thickening of the right ventricle as well due to the heart working harder to pump a backlog of unoxygenated blood from the lungs. Fundamentals 2: 11:00am-12:00pm Scribe: Susanna Pischek 5

Tuesday, October 20, 2009 Proof: Matthew Davis

Dr. Ken Waites Lung: Tuberculosis

During the course of a routine physical examination two months prior to admission, this 57- year-old white male was noted to have a lesion in the upper lobe of the right lung. Initially, he was treated for two weeks with ampicillin. He was then admitted to an outside hospital for further study. All studies including sputum studies for tubercle bacilli, bronchial washings, and bronchoscopy were negative and he was discharged. Review of systems revealed the presence of mild dyspnea on exertion, accompanied by a slightly productive cough. Of interest was the fact that the patient had been PPD positive for the past 4 to 5 years, but this had never been evaluated. On this hospital admission, physical and laboratory examinations were negative. Radiographic examination of the chest revealed a 2 x 2-cm density in the right lower lung field. Several small cavities were identified in this area on CT scan.

Autopsy Findings

The patient underwent a thoracotomy, at which time a portion of the upper lobe of the right lung was removed. Examination of the cut surface revealed small white nodules measuring up to 0.2 cm in diameter.

Looking at image 5, this is a high-power (oil immersion) photomicrograph of granuloma stained with an acid-fast stain, you can tell that mycobacterium tuberculosis bacilli is present since they stain red.

Kidney: Glomerulonephritis

This 17-year-old white male had end-stage renal disease requiring hemodialysis for 10 years. For the previous four years he had hypertension which slowly increased to about 180/120 mm Hg. Laboratory findings included a greatly elevated BUN and creatinine. He was admitted for bilateral nephrectomy and discharged in satisfactory condition on the 10th postoperative day. He was to be contacted in the future for transplantation.

Autopsy Findings

The left (97 grams) and right (88 grams) kidneys were of similar appearance. Cortices were pale, diffusely granular with a few 1-2 mm cysts. On being sectioned, the cortex of each kidney was thin (4-5 mm) and pale. Renal medullae were pale yellow-tan in color and there was abundant peripelvic fat. The ureters, pelvis, calyces and hilar vessels showed no abnormalities.

Looking at image 2, you can see that this is a higher-power photomicrograph of hyalinized glomeruli (arrows) and glomeruli with thick basement membranes. Image 4 depicts a photomicrograph of interstitial and vascular lesions in end stage renal disease. Image 7 is a photomicrograph of a glomerulus from another case with acute poststreptococcal glomerulonephritis. In this case the immune complex glomerular disease is ongoing with Fundamentals 2: 11:00am-12:00pm Scribe: Susanna Pischek 6

Tuesday, October 20, 2009 Proof: Matthew Davis

Dr. Ken Waites necrosis and accumulation of neutrophils in the glomerulus. In image 8, an immunofluorescent photomicrograph of a glomerulus from a case of acute poststreptococcal glomerulonephritis shows a granular immunofluorescence pattern consistent with immune complex disease. The primary antibody used for this staining was specific for IgG; however antibodies for complement would show a similar pattern.

Kidney: Acute Transplant Rejection

This 34-year-old white male with end-stage chronic glomerulonephritis had been receiving hemodialysis three times per week for 4 months when he was admitted to the hospital for a living related-donor transplantation from his mother. Other than the kidney disease, the patient was in good health. The transplant was performed successfully with no complications. However, eight days later, transplant rejection necessitated returning the patient to the operating room for a nephrectomy of the transplanted kidney. After the nephrectomy, the patient did quite well, was returned to hemodialysis, and was discharged home in good condition.

Autopsy Findings

The kidney weighed 240 grams and was edematous. The capsule stripped with ease to reveal a pale tan-brown cortex which was irregularly red-mottled. Upon sectioning, the cortical band was ill-defined, and the corticomedullary junction was not well-demarcated. The renal papillae were edematous and the renal pelvis displayed generalized petechial hemorrhages which extended through the 7-cm segment of ureter to a diffusely hemorrhagic terminal portion.

Briefly discussed the images. Be sure to note the difference between the micrograph images in acute transplant rejection and chronic transplant rejection. There is a marked loss of renal tubules throughout chronic transplant rejected tissue with replacement by fibrous connective tissue. Also note the cellularity of the glomeruli in chronic transplant rejection.

Kidney: Chronic Transplant Rejection

This 39-year-old male had malignant hypertension with malignant nephrosclerosis, progressing to chronic renal failure. He underwent a bilateral nephrectomy for control of his hypertension and received a cadaveric renal transplant. He did well, although he developed diabetes mellitus and had persistent, but less severe controllable hypertension. Two years following transplantation he was admitted to the hospital for control of his hypertension and evaluation of his chronic rejection. Initial blood pressure while in the hospital was in the range of 160/110 to 160/100 mm Hg. He was placed on a more intensive hypertension regimen, and he gradually became normotensive. He received one hemodialysis treatment prior to discharge. At the time of discharge, his blood pressure was 100 to 110 over 60 to 70 and he was doing well on dialysis. His BUN was 113 mg/dL and creatinine 5.2 mg/dL, and he had a hematocrit (PCV) of 27%. The patient was again admitted one month later for evaluation of azotemia and for control of his Fundamentals 2: 11:00am-12:00pm Scribe: Susanna Pischek 7

Tuesday, October 20, 2009 Proof: Matthew Davis

Dr. Ken Waites hypertension. It was felt that his chronic rejection was end-stage and that he would have to be dialyzed periodically. He was put on a renal failure diet, and over the period of his hospitalization, his BUN and creatinine finally stabilized at high levels. He tolerated dialysis well, and a transplant nephrectomy was done at 2 1/2 years post transplant. At the time of discharge, the patient's BUN was 78 mg/dL, creatinine 3.6 mg/dL, WBC 5000 cells/cmm, and the PCV was 26%.

Autopsy Findings

The kidney weighed 215 grams and was covered by a thick capsule, which was partially adherent to the cortex, but could be stripped from the kidney with slight difficulty. The calyces and pelvis of the kidney appeared normal. The vessels were not prominent. The renal arteries and vein appeared normal.

Note the differences between acute and chronic transplant rejection as exhibited in images 3 and 10.

Multiple Myeloma with Amyloid

This 63-year-old female presented with the complaint of left chest pain of approximately 4 months duration. Physical examination revealed that the pain was along the distribution of the left sixth intercostal nerve. Chest film showed a posterior mediastinal mass with partial collapse of T6. A lytic lesion of the right distal clavicle was noted on subsequent radiological examination. A bone scan revealed increased uptake in thoracic vertebrae. Serum alkaline phosphatase was elevated slightly (143 U/L). Serum protein electrophoresis was normal, while urine protein electrophoresis showed a monoclonal spike in the Gamma region. A bone marrow study was non-diagnostic.

Autopsy Findings

A thoracotomy was performed after an unsuccessful needle biopsy. At thoracotomy, a 3-cm posterior mediastinal mass was identified that extended to within 1-2 mm of the aorta and into the interspace between the ribs.

Image 4 is a photograph of the vertebral column from this patient at autopsy. Notice the collapsed vertebra (1). There are multiple variably-sized white nodules (2) within the bone marrow. These are accumulations of malignant plasma cells in this case of multiple myeloma.

Liver: Amyloidosis

This 46-year-old white male with a long-standing history of rheumatoid arthritis was admitted for treatment of pneumonia. Subsequently, complications associated with lung abscesses, empyema, and septicemia led to the patient's death. Fundamentals 2: 11:00am-12:00pm Scribe: Susanna Pischek 8

Tuesday, October 20, 2009 Proof: Matthew Davis

Dr. Ken Waites

Autopsy Findings

The liver weighed 2600 grams. It was yellowish-tan in color and cut with difficulty (fibrosis?). No other pathological changes were noted except for pneumonia and lung abscesses.

In image 6 it was emphasized that in this low-power photomicrograph of liver tissue, the stain was with Congo red (orange color in slide). Congo red reacts with amyloid and gives it an orange color (arrows). It is important to note in image 11 the photomicrograph of the tongue demonstrates extensive amyloid deposits (1) separating the skeletal muscle fibers of the tongue. In many cases the amyloid encircles the muscle fibers (2) and these muscle fibers are atrophied. It is much easier to get a biopsy of the tongue than the liver; therefore, you can pull back the tongue and exam it and take a tissue biopsy of it to see what is happening to the liver tissue.

Heart: Senile Amyloidosis

This 87-year-old black male diabetic was admitted for amputation of the lower extremity involved by atherosclerotic gangrene and osteomyelitis. Following amputation, the patient's course was one of progressive deterioration. Laboratory studies immediately prior to death revealed a blood glucose of 840 mg/dL and a serum CO2 (bicarbonate) of 8.5 mmol/L.

Autopsy Findings

The heart weighed 540 grams. The endocardial surface of both atria presented a mottled gray- red and gray-white appearance. Multiple sections through the myocardium revealed a marked 'pallor' of the muscle.

The images were briefly discussed, but it is best to look back over them, as well as the rest of the labs one more time for thoroughness. Dr. Waite wanted the class to realize the importance of reading through the internet laboratories carefully.