| Disease | Most Frequent Clinical Presentation | Pathogenesis | Light Microscope | F.M. (Fluorescence
Microscope)
E.M. (Electron Microscope) |
Age Group Affected | Treatment and
Outcome | |
 |
Minimal Change Disease |
|
|
Normal
Lipid in tubules |
F.M. = negative
E.M. = loss of foot processes, lipid vacuoles |
#1 cause of Nephrotic Syndrome in children, esp. boys younger than 6 yrs. old. | Responds well to
corticosteroids.
No progression into chronic renal failure |
| Focal Segmental
Glomerular Sclerosis
(Lipoid Nephrosis) |
|
|
|
F.M. = IgM, C3
E.M. = Loss of foot processes, detachment of epithelium from B.M. |
Majority occur in older children. Also occurs in adults. | Does not respond to corticosteroids. Leads to renal failure. | |
| Membranous
Nephropathy
(Glomerulonephritis) |
|
|
|
F.M. = "Spike and Dome."
Granular IgG, C3
E.M. = Subepithelial immune deposits in B.M., thickened B.M. |
#1 cause of Nephrotic syndrome in adults | Benefit of corticosteroids is unknown. | |
| Diabetic
Nephropathy
(Diabetic Glomerulosclerosis) |
|
|
|
F.M. = negative
E.M. = massive mesangial growth, thickened B.M. |
Diabetics | Progresses to renal failure | |
| Renal Amyloidosis | Subendothelial and mesangial amyloid deposits |
|
F.M. = negative
E.M. = characteristic criss-cross fibrillary proteins. |
Any age group | Severe amyloid infiltration leads to renal failure | ||
 |
Alport Syndrome
(Hereditary Nephritis) |
|
Structural defect in Collagen IV leads to leaky basement membranes. | Looks normal | F.M. = negative
E.M. = glomerular B.M. splitting |
Symptoms appear before age 20 | Progresses to renal failure |
| Benign Familial
Hematuria
(Thin B.M. Disease) |
|
Reduced thickness of glomerular B.M. | Looks normal | F.M. = negative
E.M. = reduced glomerular B.M. thickness |
|||
| Acute (Post-Streptococcal) Glomerulonephritis |
|
|
|
F.M. = "lumpy-bumpy"
granular deposits of IgG and
C3
E.M. = Subepithelial (not subendothelial) "humps," otherwise normal appearing B.M. |
Common renal disease in childhood | Return to normal in 8
weeks.
Complete recovery without treatment (especially in kids) within 3 years. | |
| SLE Nephropathy | Degree of kidney involvement correlates with prognosis in SLE. | Anti ds-DNA antibodies. |
|
F.M. = IgM, IgG + C3
|
|||
| Focal Segmental Glomerulonephritis | IgA Nephropathy (Berger's Disease): Most common primary glomerulonephritis | Circulating IgA + fibronectin (due to chronic liver disease) |
|
F.M. = Granular
appearance, IgG + C3
E.M. = Mesangial deposits |
Young men 15-30 | ||
| Henoch-Schonlein Purpura | Same as above, plus systemic disease: purpura of extremities, arthritis, colicky abdominal pain. |
|
F.M. = Granular
appearance, IgG + C3
E.M. = Mesangial deposits |
Children | |||
| Endocarditis | S. Aureus |
|
F.M. = Granular appearance, IgG + C3 | Kidney disease resolves when infection is cured. | |||
| Rapidly Progressive Crescentic Glomerulonephritis |
|
|
|
F.M. = Pauci-immune.
Irregular
E.M. = wrinkling, discontinuity of B.M. |
Must be treated or it will go to renal failure within weeks. | ||
| Goodpasture
Syndrome
(Anti-BM Antibody Disease) |
Lung (hemoptysis) + kidneys (hematuria) | Anti-B.M. antibodies, against Type-IV collagen | Similar to Crescentic glomerulonephritis, as above. | F.M. = Linear pattern, IgG
+ C3
E.M. = No immune complex deposits |
Males 25-30 | Responds to immunosuppressive therapy and plasmapheresis | |
| Membranoproliferative
Glomerulonephritis
(Mesangiocapillary Glomerulonephritis) |
|
E.M. = "Tram-track" appearance, resulting from double-layer appearance of glomerular B.M. |
NORMAL STRUCTURE:
A) Three areas of narrowing:
1) Cricopharyngeus muscle
2) Compression near the arch of the aorta
3) At the esophageal hiatus (diaphragm)
B) Musculature:
1) Upper Third: Skeletal Muscle
2) Middle Third: Skeletal + Smooth
3) Lower Third: Smooth Muscle
C) Layers of the Esophagus:
1) Non-Keratinized Squamous Epithelium
2) Lamina Propria
3) Muscularis Mucosa
4) Submucosa
Submucosal Plexus
5) Muscularis Externa
Muscularis Circularis
Myenteric Plexus
Muscularis Longitudinalis
6) Adventitia
CONGENITAL DISORDERS:
A) TRACHEO-ESOPHAGEAL FISTULA:
1) PATHOGENESIS: Congenital anomaly, often associated with Esophageal Atresia and congenital heart disease
2) THREE FORMS:
Most Common Form (90%): Upper esophagus ends in blind non-descript pouch. Lower esophagus is then connected to trachea.
3) CLINICAL: Associated with high mortality.
COMPLICATION: Aspiration Pneumonia in the infant is worse complication. Milk is regurgitated and then aspirated.
TREATMENT: Surgery is sometimes possible.
RINGS and WEBS:
B) PLUMMER-VINSON (PATERSON-KELLY) SYNDROME:
1) PATHOLOGY: Cervical Esophageal Web is an indentation of esophageal mucosa in neck, impeding flow.
Will also find glossitis; mucosal lesions of mouth and pharynx.
Iron-deficiency anemia is almost always also found.
2) CLINICAL:
Dysphagia is most common symptom.
COMPLICATION: Carcinoma of the mouth and oropharynx is common.
C) SCHATZKI RING: Narrowing at gastroesophageal junction (between squamous and columnar epithelium). It is only
rarely symptomatic.
ESOPHAGEAL DIVERTICULA:
A) ZENKER DIVERTICULUM: Outpocketing of the upper esophagus between cricopharyngeus and pharyngeus muscles.
1) CLINICAL: Outpocketing creates a blind pouch, which accumulates food ------> halitosis.
Usually seen in elderly patients.
B) TRACTION DIVERTICULUM: Pulling of the esophagus, caused by scars or fibrosis.
C) EPIPHRENIC DIVERTICULUM:
MOTOR DISORDERS:
A) ACHALASIA: Stenosis of the Lower Esophageal Sphincter ------> Megaesophagus.
1) PATHOGENESIS: Thought to be a congenital degeneration of the Myenteric (Auerbach's) Plexus, such that the lower esophagus is unable to fully relax.
Three characteristic abnormalities:
Increased LES Pressure.
Inability for lower esophagus to relax.
Aperistalsis of lower esophagus.
Acquired Megaesophagus can be caused by the parasite Trypanosoma Cruzi (Chagas Disease)
2) CLINICAL: Symptoms are dysphagia, regurgitation, megaesophagus, and aspiration pneumonia.
B) SCLERODERMA: Effects principally the lower esophageal sphincter.
HIATAL HERNIA:
A) PATHOGENESIS:
1) SLIDING HERNIA: Standard hiatal hernia. Slippage of the gastric cardia upward through the Esophageal Hiatus.
2) PARA-ESOPHAGEAL HERNIA: Herniation of the gastric cardia through a defect in the diaphragmatic membrane (next to the esophagus), rather than through the Hiatus itself.
B) CLINICAL: Hiatal hernias usually present as GERD. They don't know whether the GERD causes the hernia, or vice-versa.
Each one begets the other.
ESOPHAGITIS:
A) PATHOGENESIS: Multiple causes
1) GASTRO-ESOPHAGEAL REFLUX DISEASE (GERD): Incompetent lower esophageal sphincter; regurgitation of stomach contents.
2) INFECTIOUS AGENTS: Can be seen in immunocompromised: AIDS, Diabetes, Lymphomas.
Candida is most common.
Can visualize it by using a silver stain, which colors the candidal hyphae black.
CMV is second most common.
Herpes Zoster, HSV can also be seen.
3) Uremia
4) Iatrogenic: Radiation, chemotherapy, prolonged intubation.
5) CHEMICAL: Acids or bases can damage the esophageal epithelium, but particularly bases, lye, causes the worst damage.
Alkaline Injury: Produces liquefactive necrosis, thrombosis, and saponification of lipids in the region.
B) PATHOLOGY:
1) Basal Zone Hyperplasia: Basal zone proliferates, going from 10% to ~20% of esophageal mucosa.
2) Elongated Papillae
3) Inflammatory Cells: Eosinophils are almost always found between epithelia. PMN's may or may not be found.
4) Leukoplakia: General thickening of the epithelium, seen as white patches.
C) COMPLICATIONS:
1) Ulceration: Ulcers can heal, leaving behind scars and possibly strictures.
2) Strictures can occur with chronic esophagitis ------> scarring.
3) BARRETT ESOPHAGUS: Squamous ------> Columnar Metaplasia of esophageal epithelium.
Esophageal Adenocarcinoma develops in 5-10% of people with Barrett Esophagus.
Esophageal epithelium can change to gastric or intestinal epithelium. Intestinal epithelium carries a higher chance of becoming cancerous.
ESOPHAGEAL VARICES: Lower Esophagus. Portal-caval anastomoses of the esophageal arteries, which become dilated in portal
hypertension, and often rupture.
ESOPHAGEAL CANCER:
A) EPIDEMIOLOGY: Most prevalent in China. 60% of all cases come from China.
B) PATHOGENESIS: Long list of predisposing conditions and risk-factors.
1) RISK-FACTORS: Alcoholism and Smoking are the big ones.
Nitrosamines: maybe, but evidence is lacking.
Diet: Low in fresh fruits and vegetables. Again, this is possible, but evidence lacks.
2) PREDISPOSING CONDITIONS:
Chronic Esophagitis: Anything causing chronic esophagitis can lead to cancer.
GERD
Plummer Vinson Syndrome
Achalasia
Esophageal Stricture
Rings and Webs.
Barrett Esophagus: Columnar dysplasia is a risk-factor for development of adenocarcinoma only.
Squamous Dysplasia: Pre-cancerous epithelium at risk for turning into squamous cell carcinoma only.
C) CLINICAL: Very poor survival due to late detection. Once it becomes symptomatic, cancer has usually already spread to lymph nodes.
D) SQUAMOUS CARCINOMA: Most common type. 70-90%
1) CLINICAL: Can treat with radiation therapy.
2) PATHOLOGY: Three morphological types:
Polypoid: Projects into esophageal lumen.
Ulcerating
Infiltrating: Spreads through esophageal wall.
E) ADENOCARCINOMA: Next most common type. 10-20%
1) CLINICAL: Radiation therapy doesn't really help that much.
2) PATHOGENESIS: Almost always arise from Barrett Esophagus. Barrett esophagus can lead to adenocarcinoma -- but not squamous!
F) OTHER CANCERS: Very rarely seen
1) OAT CELL CARCINOMA
2) MELANOMA
NORMAL STRUCTURE:
A) BODY / FUNDUS: The pits are short and the glands are long and straight. High gland:pit ratio.
1) Parietal Cells which secrete acid are found mostly in the body of the stomach.
2) Also contains Chief Cells (secreting Pepsin)
B) ANTRUM: The pits are long and the glands are short. Small gland:pit ratio.
1) Contains Chief Cells, but very few Parietal Cells.
CONGENITAL DISORDERS:
A) CONGENITAL PYLORIC STENOSIS:
1) EPIDEMIOLOGY: Fairly common. Male:female ratio of 4:1.
2) PATHOGENESIS: Congenital hypertrophy and hyperplasia of the smooth muscle of the pyloric sphincter, resulting in little or no gastric emptying.
3) SYMPTOMS: Symptoms appear by 3-4 weeks of age.
Projectile Vomiting: The vomit does not contain bile (it never reaches duodenum).
Voracious Appetite.
Hypochloremic Alkalosis: Low HCl with metabolic alkalosis, due to loss of gastric juices because of vomiting.
Visible peristaltic movements can be seen, and a palpable lump is felt near the pylorus.
4) TREATMENT: Pyloromyotomy. Surgical incision made along the length of the pylorus. Usually curative.
GASTRITIS:
A) ACUTE (EROSIVE) GASTRITIS: Short-term, reversible necrosis in the stomach.
1) PATHOGENESIS: Long list of causative agents.
Alcohol
NSAID's: Inhibit prostaglandins ------> lost protection of gastric mucosa.
CUSHING ULCER: Trauma to CNS, or CNS surgery. Ulcers are typically deep and can perforate.
CURLING ULCER: Gastric ulcer from extensive third-degree burns.
Shock or sepsis ------> gastric ischemia ------> acute ulcer.
2) PATHOLOGY: Patchy mucosal necrosis. Ulcers vary in size and distribution.
B) CHRONIC (NON-EROSIVE) GASTRITIS:
1) PATHOLOGY: Three progressive stages of chronic gastritis, common to both forms.
Superficial Gastritis: Just superficial mucosa.
Atrophic Gastritis: Inflammation becomes transluminal, and mucosa becomes flattened. The inflammatory cells can leave, leaving behind a thin mucosa ------> Gastric "atrophy"
Intestinal Metaplasia: Similar to Barrett Esophagus, this metaplasia is pre-cancerous.
2) SYMPTOM: Dyspepsia is the common symptom of chronic gastritis. It is a very non-specific finding.
3) AUTOIMMUNE GASTRITIS:
PATHOGENESIS: Autoantibodies against parietal cells, against intrinsic factor, or against both.
PATHOLOGY: Typically involves the fundus of the stomach (where the Parietal cells are). The antrum is spared.
CLINICAL:
Pernicious (Megaloblastic) Anemia is seen, due to loss of intrinsic factor ------> no absorption of Vit B-12 in ileum.
Hypergastrinemia: Acid secretion is deficient, and Gastrin levels are therefore elevated.
4) CHRONIC ANTRAL (IDIOPATHIC) GASTRITIS: Chronic gastritis of unknown cause. Chronic idiopathic gastritis is a risk-factor for Stomach Cancer.
PATHOGENESIS: Idiopathic.
PATHOLOGY: Inflammation starts at the antrum and spreads proximally. Degree of inflammation varies from superficial to gastric atrophy.
CLINICAL:
No pernicious anemia is seen.
May see an excess or deficiency of HCl.
Gastrin levels and acid secretion are normal.
5) INFECTIOUS GASTRITIS: Usually caused by H. Pylori, it is a precursor to Peptic Ulcer Disease of either the stomach or duodenum
(see PUD).
MENETRIER'S DISEASE (HYPERTROPHIC GASTROPATHY):
A) EPIDEMIOLOGY: Rare. 4 times more common in men.
B) PATHOGENESIS: Idiopathic.
C) PATHOLOGY: Extra large rugae (folds) in the stomach lead to a loss of plasma proteins through the stomach mucosa.
1) May see cystic dilatation of foveolae.
D) SYMPTOMS: Sometimes present as postprandial pain.
1) May see symptoms similar to cancer (due to loss of plasma proteins): Cachexia, weight loss, edema.
2) COMPLICATION: Increased risk of Gastric cancer occurs with Menetrier's Disease.
PEPTIC ULCER DISEASE (PUD): Breaks in the mucosa of the antrum, pylorus, or proximal duodenum, caused by gastric secretions.
A) PATHOGENESIS: Helicobacter Pylori is the cause in the majority of cases.
1) Gastric acid secretion is required to cause it. Thus Autoimmune Gastritis never leads to PUD!
2) RISK-FACTORS: Things that are associated withy PUD
Smoking and alcohol
NSAID's and corticosteroids.
Blood Type O
3) PREDISPOSING CONDITIONS: Diseases associated with PUD
Zollinger-Ellison Syndrome: Hypergastrinemia causes PUD
Hyperparathyroidism ------> increased Ca+2 ------> increased Gastrin and PUD
COPD ------> increased pCO2 ------> increased Gastrin and PUD
B) PATHOLOGY: Ulcers occur in both duodenum and stomach.
1) MORPHOLOGY: Grossly, you see sharp, clean borders with "punched out" appearance. This distinguishes an ulcer from an ulcerating, malignant carcinoma. Histologically, there are four layers:
Fibrinous Exudate is the inner layer, on luminal surface.
Inflammatory cells and PMN's are beneath this.
Granulation tissue is found next
Fibrotic tissue is found at the base of the ulcer, with various levels of chronic inflammation.
2) DUODENAL ULCERS:
H. Pylori is always found in duodenal ulcers. It is a necessary condition for duodenal ulcers.
The bugs are found in islands of gastric mucosa within the duodenal bulb. They are thought to induce gastric metaplasia in the duodenum, and then subsequently infect the metaplastic area.
Duodenal ulcers never become malignant.
3) GASTRIC ULCERS: H. Pylori may or may not be found in gastric ulcers.
C) CLINICAL:
1) SYMPTOMS: Patient will have epigastric pain made worse by food, aspirin, and alcohol.
May have hematochezia (occult blood in stool) or hematemesis.
GI blood is possible.
2) COMPLICATIONS:
Pyloric Obstruction is a possible complication, in which case patient will have anorexia, early satiety, and a succussion splash during fasting.
Perforation of ulcer has high mortality.
PUD do not become malignant, particularly in the duodenum.
BENIGN NEOPLASMS:
A) LEIOMYOMA: Benign smooth muscle tumor.
B) EPITHELIAL POLYPS:
1) HYPERPLASTIC POLYPS: The vast majority of gastric polyps are hyperplastic. Their origin is uncertain (sometimes from chronic inflammation), and they have no malignant potential.
2) HAMARTOMATOUS POLYPS: Mixed-tissue polyps with no malignant potential.
3) ADENOMATOUS POLYPS: They do have malignant potential and are similar to adenomatous polyps in the colon.
Villous Adenomas: Finger-like structure. They tend to become malignant more often than the tubular adenomas.
Tubular Adenomas: Pedunculated, gland (acinar)-like structure.
MALIGNANT NEOPLASMS:
A) ADENOCARCINOMA of the STOMACH:
1) EPIDEMIOLOGY: Incidence is high in Japanese population. It used to be high in U.S. but is now continually decreasing.
2) PATHOGENESIS:
RISK-FACTORS:
Genetic predisposition.
Blood Group A
Nitrosamines
PRE-DISPOSING CONDITIONS: The same conditions that cause intestinal metaplasia may lead to gastric cancer.
Chronic Gastritis: Either Idiopathic or Autoimmune.
Menetrier's Disease: Hypertrophic gastropathy
Partial Gastrectomy: The gastric stump is at risk of becoming malignant.
Gastric adenomatous polyps (but not hyperplastic polyps)
3) PATHOLOGY:
Multiple types of gastric tumors
Polypoid Adenocarcinoma: Solid mass projects into lumen of stomach.
Ulcerating Adenocarcinoma: Tumor forms an ulcer, with epithelium "overgrowing" around the edges.
This must be distinguished with a benign ulcer, which has sharp, "punched-out" edges.
Diffuse (Infiltrating) Adenocarcinoma: No solid tumor, but instead neoplasm infiltrates throughout the mucosa of the stomach, making the stomach wall thicker.
Invading tumor cells cause intense fibrosis of the stomach, and cause the wall to become very thick.
LINITIS PLASTICA: "Leather-bottle stomach," when the entire stomach is subjected to infiltrating carcinoma.
Signet Ring Cell: Gastric tumor cells have lots of mucin, which displaces the nucleus to the periphery, giving it this characteristic appearance.
4) CLINICAL:
COMPLICATIONS:
KRUKENBERG TUMOR: Metastases to the ovaries. The metastases can come from any primary site, but often originates as a gastric adenocarcinoma.
B) OTHER CARCINOMAS: Much rarer
1) ADENOSQUAMOUS CARCINOMA
2) ENDOCRINE-CELL TUMORS
3) CHORIO-CARCINOMA:
C) GASTRIC LYMPHOMA:
CONGENITAL DISORDERS:
A) ATRESIA AND STENOSIS:
1) ATRESIA: Complete occlusion of the intestinal lumen. Three subtypes:
Fibrous Diaphragm forms in the lumen of the bowel, creating a complete obstruction.
Complete Fibrosis of a segment of the bowel can leave the surrounding segments connected by a string-like cord.
Complete Separation between two sections of bowel. Walls completely close off each end.
2) STENOSIS: Narrowing or stricture of the intestinal lumen.
3) CLINICAL: Babies with congenital atresia or stenosis will have failure to pass meconium.
TREATMENT: Surgery is usually curative, but other anomalies can coexist.
B) MECKEL DIVERTICULUM: Most common congenital anomaly of small intestine.
1) CLINICAL: RULE of 2's
2 inches long
2% of population (some say 10%)
2 feet proximal to the ileocecal junction
2) COMPLICATIONS: Diverticulum can contain ectopic secretory tissue: gastric tissue, endocrine tissue, biliary tissue, pancreatic, etc.
Gastric metaplasia ------> secrete Gastrin ------> ulcer at the site of the Diverticulum.
C) MECONIUM ILEUS:
INFECTIONS:
A) BACTERIAL DIARRHEA:
B) VIRAL GASTROENTERITIS:
C) TUBERCULOSIS:
D) PARASITIC INFECTIONS:
VASCULAR DISEASES:
A) ACUTE INTESTINAL ISCHEMIA: Often caused by mechanical obstruction, but can be caused by other things, too.
1) PATHOGENESIS: Mechanical obstruction is one main cause. Other causes:
Thromboembolism to bowel.
Arteritis, vasculitis
B) CHRONIC INTESTINAL ISCHEMIA: Caused by hypotension or atherosclerotic narrowing of splanchnic arteries.
MALABSORPTION:
A) PATHOGENESIS:
1) Luminal-Phase Malabsorption: Failure to digest food in the lumen, caused by pancreatic insufficiency, bile obstruction or biliary insufficiency (fail to absorb fats), bacterial overgrowth.
2) Intestinal Phase Malabsorption: Failure to absorb nutrients at the brush border, caused by Celiac Disease, Tropical Sprue, Whipple Disease, and Lactase Deficiency.
B) CELIAC DISEASE (CELIAC SPRUE): Also known as Gluten-Sensitive Enteropathy
1) PATHOGENESIS: Antibodies to gliadin, the breakdown byproduct of gluten which is found in wheat and rye.
IMMUNITY: Genetic predisposition, plus exposure to a virus (Adenovirus 12) causes antibodies to be formed against gliadin.
GENETIC PREDISPOSITION: HLA-B8 (class I) and HLA-DR3, HLA-DQw2 (class II) are found in high percentage in patients with the disease.
2) PATHOLOGY: Autoimmune attack against Gliadin ------> loss of intestinal villi and flattening of mucosa ------> malabsorption at the brush border.
Flattened, blunted villi.
Hyperplastic crypts, with chronic inflammatory cells found between the crypts.
No glycocalyx border.
3) CLINICAL: Diarrhea, malabsorption, anemia, weight loss.
DIAGNOSIS: D-Xylose Absorption Test. Give 25 gms of xylose is orally and measure urinary excretion of xylose in the next 5 hours. Should be at least 5 grams of xylose excreted, but it is lower in sprue and other malabsorptive syndromes.
TREATMENT: Withhold gluten from diet.
C) TROPICAL SPRUE: Progressive malabsorption of obscure etiology.
1) PATHOGENESIS: Enterotoxigenic E.Coli (ETEC) and Folate Deficiency have been implicated in pathogenesis.
2) TREATMENT: Give tetracycline (for the bugs) and folate.
D) WHIPPLE DISEASE: Infection with Tropheryma Whipplei.
1) CLINICAL: Symptoms are arthritis, joint swelling, fever, weight loss, diarrhea
2) PATHOLOGY: Foamy macrophages in the intestinal brush-border are the pathognomonic sign of Whipple Disease.
Macrophages have a basophilic, granular cytoplasm and are filled with the T. Whipplei, intracellular parasites.
E) LACTASE DEFICIENCY:
MECHANICAL OBSTRUCTION: Mechanical obstructions can lead to ischemic bowel disease.
A) INTUSSUSCEPTION: Occlusion in which a segment of bowel protrudes distally into the outer portion of the next segment of bowel, just like the segments of a telescope.
1) COMPLICATION: Can lead to ischemic bowel injury.
B) VOLVULUS: A segment of gut twists on its mesentery, cutting off the blood supply and resulting in acute ischemia.
1) PATHOGENESIS: Consequence of underlying congenital abnormality.
2) CLINICAL: Presents as acute abdomen, with a cut off blood supply.
BENIGN NEOPLASMS:
A) ADENOMAS
B) PEUTZ-JEGHERS SYNDROME:
1) PATHOGENESIS: Autosomal dominant hereditary disorder.
2) PATHOLOGY:
Hamartomatous Polyps: Benign polyps, consisting of glandular epithelium and smooth muscle.
3) CLINICAL:
SYMPTOMS: Mucocutaneous Pigmentation of the skin is seen in face, buccal mucosa, hands, feet, and perineum.
COMPLICATIONS: 2% of patients will develop adenocarcinoma of the stomach, breast, or ovary.
MALIGNANT NEOPLASMS:
A) ADENOCARCINOMA: The tumors are often annulars, thus the symptoms are often those of progressive bowel obstruction.
B) PRIMARY LYMPHOMA:
1) PATHOGENESIS: Associated with Celiac Disease is well established.
2) CLINICAL: Mediterranean Lymphoma
C) CARCINOID TUMOR: Ectopic, secretory tumor found in small intestine, appendix, or colon.
1) CLINICAL: Carcinoid Syndrome results from excessive secretion of serotonin and/or bradykinin from the tumor.
Right Heart Failure
Sweating, flushing
Cyanosis
Hypertension
Diarrhea
2) DIAGNOSIS: Look for 5-hydroxy-indole acetic acid in urine, a metabolite of serotonin.
D) MEDITERRANEAN LYMPHOMA: Immuno-proliferative disorder of the small intestine in which the plasmacytoid
lymphocytes synthesize one of the heavy chains of the immunoglobulins ( commonly it is the alpha chain, hence called
alpha chain disease )
THE APPENDIX:
E) ACUTE APPENDICITIS:
1) PATHOGENESIS: Intestinal ischemia in the appendix is often the cause of the infection. Content increase the pressure in appendix ------> cut off blood supply ------> ischemia, which predisposes to infection.
2) PATHOLOGY: Infected appendix is covered with fibrinous exudate when removed.
3) CLINICAL: Presents as acute abdomen. Sharp RLQ pain, leukocytosis with left shift.
F) MUCOCELE: Distended appendix with lots of mucus inside.
1) PATHOLOGY: Can be benign or malignant. Look at underlying epithelium to distinguish.
2) COMPLICATION: Pseudomyxoma Peritonei occurs when the mucocele leaks into the peritoneum. Epithelial cells can seed in the
peritoneal wall and create these little polyps of mucus-secreting tumor cells.
CONGENITAL DISORDERS:
A) HIRSCHSPRUNG DISEASE (CONGENITAL MEGACOLON):
1) PATHOGENESIS: Defect in the innervation of the rectum, resulting in failure of relaxation of the anal sphincter. Very similar to Achalasia.
Acquired Megacolon can be caused by the parasite Trypanosoma Cruzi (Chagas Disease)
B) ANORECTAL MALFORMATIONS:
INFECTIONS:
A) PSEUDOMEMBRANOUS COLITIS: Clostridium Difficile infection resulting from antibiotic therapy.
1) PATHOGENESIS: The inflammation is caused by a toxin elaborated by C. Difficile -- not by the bug itself.
Antibiotics kill intestinal flora, resulting in overgrowth of C. Difficile. Suspect antibiotics:
Clindamycin
Penicillins
Cephalosporins
Aminoglycosides
2) PATHOLOGY: Multiple dot-like
B) NEONATAL NECROTIZING ENTEROCOLITIS: Clostridium Perfringens
DIVERTICULAR DISEASE:
A) DIVERTICULOSIS: Herniation of mucosa and submucosa through the muscular layers of the colon.
1) PATHOGENESIS: Lack of fiber in diet is believed to be a strong causative factor.
2) PATHOLOGY: Almost always occurs in sigmoid colon.
B) DIVERTICULITIS: Inflammation at the base of a diverticulum.
1) PATHOGENESIS: Presumed to be caused from retained fecal material in a diverticulum.
2) CLINICAL: Perforation is very common, but it usually only leads to a localized abscess (restricted by neighboring organs, the
mesentery, or adhesions). It can, however, lead to generalized peritonitis.
INFLAMMATORY BOWEL DISEASE:
A) EPIDEMIOLOGY: Highest prevalence in U.S. and European countries. Incidence has increased in modern times, pointing to dietary and environmental factors as causative factors.
1) Age-Distribution: Peak around 20-25 years of age, with another peak in the 60's.
2) Seen more frequently in whites than in blacks.
B) PATHOGENESIS: Diseases are idiopathic, with environmental and possible immune factors playing a role.
1) General risk-factors for inflammatory bowel disease
Stress of urban life style.
Smoking has been found to have a beneficial effect for Ulcerative Colitis, statistically. However, for Crohn's Disease is was found to be detrimental.
C) CROHN DISEASE: Chronic granulomatous inflammation of the bowel wall, with unknown etiology.
1) PATHOLOGY: Transmural inflammation of the bowel wall occurs.
Skip-Lesions are found, where normal sections of intestine are interspersed with inflamed sections. Inflammation is interspersed and periodic.
Non-caseating granulomas are found in Crohn's Disease
Anatomic distribution is variable: can be found anywhere from mouth to anus.
45%: Terminal ileum and colon.
33%: Small bowel alone
25%: Colon alone
2) CLINICAL: Symptoms are abdominal pain and diarrhea, possible fever.
3) COMPLICATIONS:
Strictures may result from the transmural inflammation.
Gallstones: Crohn's Disease in the Ileum ------> poor reabsorption of bile salts ------> deficient ball salts and gallstones.
Hydronephrosis: Can result from involvement of ureter in the stricture.
CANCER: Increased risk for Squamous Carcinoma of anus and Adenocarcinoma of colon.
D) ULCERATIVE COLITIS: Chronic inflammation of the colon, essentially limited to the colonic mucosa.
1) PATHOLOGY:
Anatomic Distribution: Ulcerative Colitis always starts in the rectum and works its way proximally, often extending through sigmoid and left colon.
Inflammation is consistent throughout the mucosa: edema, denudation, and ulceration is seen throughout.
Crypt Abscesses are common.
2) CLINICAL: Rectal bleeding is very common. Fever, diarrhea, abdominal pain. Moderate anemia from blood loss.
3) COMPLICATIONS:
Toxic Megacolon: Extensive dilatation of colon, where wall is thin, friable, and subject to perforation.
Colonic Carcinoma: Increased risk for cancer with prolonged disease. Occurs because of continual regeneration of epithelia ------> intestinal dysplasia.
Usually occurs after 10 years with Ulcerative Colitis.
The type of cancer is different than colonic adenocarcinoma arising from polyps: they are often multiple and are flat lesions rather than polypoid.
E) INDETERMINATE COLITIS:
F) SYSTEMIC COMPLICATIONS: Inflammatory Bowel Diseases in general can present with several systemic complications:
1) Immune-mediated complications:
Erythema Nodosum
Pyoderma Gangrenosum
Uveitis: in eyes
Aphthous Stomatitis: inflammation in mouth.
Ankylosing Spondylitis
2) Primary Sclerosing Cholangitis is a long-term complication, which can lead to cholangiocarcinoma.
3) Adenocarcinoma: Crohn's leads to intestinal carcinoma, and UC leads to colonic carcinoma.
| CROHN DISEASE | ULCERATIVE COLITIS | |
| Anatomic Distribution | Rectal sparing.
Terminal Ileum is often involved and is very important. |
Rectum is always involved.
Terminal ileum is rarely involved. |
| Type of Inflammation | Transmural | Strictly mucosal |
| Distribution of Inflammation | Periodic Skip-lesions: Discrete ulcers with islands of normal mucosa. | No skip lesions. Diffuse inflammation and edema throughout, leading to edema and ulceration. |
| Microscopic Pathological Features | Non-caseating granulomas | Crypt Abscesses |
| Macroscopic Pathological Features | Fissures piercing through wall, which can lead to fistulas. | Thickened colonic wall early on.
Can see thin, atrophic wall in case of
toxic megacolon.
Pseudopolyps are common. |
| Complications | May see strictures
Gallstones Hydronephrosis from ureter involvement. |
No strictures are seen.
Toxic Megacolon. Many systemic complications. |
| Cancer | Intestinal Adenocarcinoma
Overall risk is slim compared to Ulcerative Colitis. |
Risk for diffuse Colonic
Adenocarcinoma (not arising from
discrete polyps)
Increased risk for cholangiocarcinoma |
VASCULAR DISEASES:
A) ISCHEMIC COLITIS:
B) ANGIODYSPLASIA: Malformed vessels in the submucosa, in the cecum and ascending colon.
1) PATHOGENESIS: Degenerative process often found in elderly. Should always be part of the differential for bloody stools in the elderly.
C) HEMORRHOIDS:
POLYPS of the COLON:
A) BENIGN POLYPS:
1) HYPERPLASTIC POLYPS:
PATHOLOGY: Serrated appearance of crypts, frequent in rectosigmoid area. Distinguished by the proliferation in the crypts.
CLINICAL: They are not themselves neoplastic, but they are often found concurrently with colon cancers.
2) JUVENILE POLYPS: Non-neoplastic polyp which can undergo torsion and cause rectal bleeding in children.
PATHOLOGY: They are hamartomas and they are never cancerous.
3) INFLAMMATORY POLYPS: "Pseudopolyps," often found in Ulcerative Colitis.
B) ADENOMATOUS POLYPS: Extensions of colonic epithelia, which may become cancerous.
1) PATHOGENESIS: They are thought to result from an over-proliferation of crypt cells. Crypts cells normally grow up the colonic villus as part of the process of normal cell-turnover. When this process grows out of control, polyps result.
2) PATHOLOGY: Two different forms.
TUBULAR ADENOMAS: Pedunculated, gland-like structures.
They are easier to fix with surgical resection. They come off easier.
VILLOUS ADENOMAS: Extensions of mucosal surface, cauliflower-like surface. More finger-like structure.
Generally, Villous Adenomas are more likely to progress to cancer.
3) CLINICAL: They are pre-cancerous. The size of the polyp correlates with the risk for cancer.
C) POLYPOSIS SYNDROMES:
1) ADENOMATOUS POLYPOSIS COLI (APC): Autosomal Dominant, progressive development of lots of adenomatous polyps in the colon.
CLINICAL: Progression to colonic adenocarcinoma is inevitable.
2) GARDNER SYNDROME: Autosomal dominant disease.
CLASSICAL SYMPTOMS:
Polyposis of GI tract, especially in colon, but it also occurs in stomach and the Ampulla of Vater.
Osteomas of skull, mandible, long bones.
Soft tissue tumors of the skin.
CLINICAL: Gardner Syndrome progresses to Colon Cancer.
ADENOCARCINOMA of the COLON:
A) PATHOGENESIS:
1) Classically, step-wise progression to cancer. Multiple genetic mutations are thought to have to occur, before a polyp becomes malignant. Genes involved:
ras gene: Oncogene that becomes cancerous when a point mutation is introduced.
p53 gene: Tumor-suppressor gene.
DCC gene: Tumor suppressor gene; "deleted in colon cancer"
2) PREDISPOSING CONDITIONS:
Inflammatory bowel disease
Congenital polyposis syndromes
B) PATHOLOGY:
1) Napkin-Ring Tumors: Constricting-type tumors, most common in the left colon. The wall thickens, narrowing the colonic lumen.
Often present with constipation due to narrowed lumen.
2) Cauliflower Tumors: More prevalent in the right colon. Tumors may ulcerate.
Usually presents with rectal bleeding.
C) CLINICAL:
1) Progression of disease
EARLY: Asymptomatic. May find occult blood in stool if you test for it.
MIDDLE: Rectal bleeding and change in bowel habits. Possible palpable mass.
LATE: Fatigue, abdominal pain, pallor, cachexia, hepatomegaly.
2) DUKE'S CLASSIFICATION: Clinical staging of colonic tumor
STAGE A: Mildest; best prognosis. Tumor confined to mucosa.
STAGE B: Tumor invades muscularis and/or serosa.
STAGE C: Metastases to regional lymph nodes.
STAGE D: Distant metastases
LOBULAR STRUCTURE:
A) LOBULE: Dividing up the liver into sections, with the Central Venule in the middle of the section, and three portal triads in a triangular arrangement around the outside.
1) Sinusoids: In the center of the lobule.
2) Kupffer Cells: Antigen-presenting cells lined along the sinusoids.
3) Fenestrae: Endothelial cells have gigantic fenestrae to allow blood-products to freely flow through the sinusoids.
4) Space of Disse: Lies between the capillary endothelial cell and the hepatocyte.
B) ACINUS: Dividing up the liver into sections, with the Portal Triad in the middle of the section, and central venules around the outside. Divided into three zones:
1) Zone 1: The region immediately surrounding the Portal Triad.
Zone is the first to get exposed to toxins from portal blood. Zone 1 cells are most affected by toxic damage.
2) Zone 2: The middle region.
3) Zone 3: The region closest to the Terminal Hepatic Venule.
Zone 3 gets the least oxygenated blood. Zone 3 cells are most susceptible to hypoxic damage.
C) Portal Triad:
1) Bile Duct: Low columnar epithelium
2) Hepatic Arteriole: Small muscular artery
3) Portal Venule: Vein, the largest structure (histologically) in the triad.
4) Limiting Plate: The hepatic cells immediately surrounding the portal triad. They form a sharp demarcation between the portal triad and the rest of the lobule.
D) COUNTERCURRENT FLOW:
1) BLOOD-FLOW: Zone-1 ------> Zone-3
Portal Vein ------> Portal Triad ------> Portal Venule ------> Terminal Hepatic Venule ------> Central Venule ------> Central Vein ------> Hepatic Vein.
Hepatocytes closest to the Portal Triad receive the most oxygenated blood. They are specialized for drug detoxification, and are most susceptible to damage from drug toxicity.
Hepatocytes closest to the Terminal Hepatic Venule receive the least oxygenated blood. They are specialized for bile production, and are most susceptible to damage in the event of hypoxia.
2) BILE-FLOW: Zone-3 ------> Zone-1
Bile is synthesized in the hepatocytes closest to the Terminal Hepatic Venule. Those cells are more specialized for bile synthesis rather than drug detoxification.
Flow = Central Venule ------> Bile Canaliculus ------> Bile Duct ------> Portal Triad ------> Hepatic Duct ------> Common Bile
Duct
LIVER ENZYMES:
A) Aspartate Aminotransferase (AST, SGOT):
1) NORMAL VALUE: 2 - 35 IU / I
2) Used to measure the degree of liver-cell membrane damage.
B) Alanine Aminotransferase (ALT, SGPT):
1) NORMAL VALUE: 0 - 45 IU/I
2) Used to estimate liver cell injury due to viral hepatitis.
C) Alkaline Phosphatase (Alk-Phos): This enzyme is normally synthesized and secreted in the bile, to aid in intestinal digestion of phospholipids.
1) NORMAL VALUE: 30 - 130 IU / I
2) Hepatitis: Alk-Phos is not elevated. Hepatocytes are dead and not synthesizing that much enzyme.
3) Cholestasis, Biliary Cirrhosis: Alk-Phos is highly elevated. Hepatocytes can't secrete the enzyme, which not only makes it back up into the blood, but also stimulates further synthesis of it by liver cells.
D) Albumin: It is a measure of compromised metabolism. It remains normal in all forms of hepatitis, and does not become
deficient until severe cirrhosis.
BILIRUBIN METABOLISM:
A) BILIRUBIN CYCLE:
1) Heme Breakdown: Heme ------> Biliverdin ------> Bilirubin.
2) Hepatocytes take up indirect bilirubin, or unconjugated bilirubin.
3) Glucuronyl Transferase: Hepatocytes conjugate Bilirubin ------> Bilirubin Glucuronide.
4) Bilirubin Glucuronide is transported into the bile canaliculus ------> secreted into intestine.
5) Intestinal bacteria convert Bilirubin Glucuronide ------> Bilirubin ------> Urobilinogen
6) Some of urobilinogen is reabsorbed in ileum ------> back to liver. Some it is excreted in feces, giving feces its brown color.
7) Urobilinogen in liver is either re-secreted (enterohepatic circulation) or enters the systemic circulation where it goes to the urine.
B) Indirect Bilirubin: Unconjugated bilirubin.
1) A high indirect bilirubin in the blood, coupled with a high total bilirubin, usually means a hemolytic jaundice.
The conjugate system is saturated and the liver and can't conjugate it all, so unconjugated bilirubin remains in the blood.
C) Direct Bilirubin: Conjugated bilirubin. Bilirubin glucuronide.
1) A high direct bilirubin in the blood means hepatitis, or an obstructive jaundice. The liver was able to conjugate the bilirubin, but could
not secrete it into the bile tracts.
JAUNDICE DISORDERS:
A) HEMOLYTIC JAUNDICE: It will show a high total bilirubin and high indirect bilirubin.
1) PATHOGENESIS: It results from any process that gives us too many dead RBC's -- either hemolytic anemia or ineffective erythropoiesis.
B) CRIGLER-NAJJAR DISEASE: Unable to conjugate bilirubin ------> high indirect bilirubin.
1) PATHOGENESIS: Absence of UDP-Glucuronyl transferase activity.
No conjugation of bilirubin ------> excessive indirect bilirubin in blood.
Autosomal recessive enzyme deficiency.
2) CLINICAL: Presents as neonatal jaundice complicated by encephalopathy (kernicterus). Death usually occurs during the first year of life.
C) GILBERT SYNDROME: Autosomal dominant unconjugated hyperbilirubinemia of unknown pathogenesis.
1) EPIDEMIOLOGY: Affects 5-10% of population, more often in males. Typically occurs after puberty.
2) CLINICAL: Asymptomatic. Jaundice is the only symptom, and it requires no treatment.
D) DUBIN-JOHNSON SYNDROME: Unable to transport bilirubin out of hepatocytes and into bile canaliculi ------> high direct bilirubin.
1) PATHOGENESIS: Autosomal recessive chronic or intermittent jaundice, due to defective intracellular transport of bilirubin.
2) PATHOLOGY: Accumulation of brown granular pigment in liver cells and Kupffer cells. It looks like hemosiderin but it is actually bilirubin.
E) NEONATAL (PHYSIOLOGIC) JAUNDICE: Innocent jaundice of the newborn, because livers aren't always ready for bilirubin conjugation in the newborn.
1) KERNICTERUS: Only in the neonate, high concentration of indirect bilirubin in the CNS, resulting in brain damage. This is a complication of physiologic jaundice, or can occur with Neonatal Hepatitis.
F) CHOLESTASIS: Impeded flow of bile.
1) PATHOGENESIS:
Intrahepatic Cholestasis: Cholestasis caused by intrinsic liver disease.
Extrahepatic Cholestasis: Cholestasis caused by extrahepatic causes, such as gallstones or pancreatic carcinoma.
2) PATHOLOGY: Brownish bile pigment found in dilated canaliculi.
Centrilobular: Bile plugs tend to be found in the middle of the lobule -- not around the portal tracts! Remember where bile is synthesized.
Feathery Degeneration: Triad of morphological findings in chronic cholestasis
Hydropic swelling of hepatocytes
Diffuse impregnation of bile pigment (both centrally and portally)
Reticulated appearance
Bile Lakes: Longstanding cholestasis, leading to destroyed hepatocytes. Bile lakes replace the destroyed cells.
3) CLINICAL: DIAGNOSIS is based on finding excessive amounts of things in the blood:
Cholesterol: Hypercholesterolemia.
Bilirubin: Both direct and indirect.
Bile Acids in blood.
Alkaline Phosphatase is usually elevated.
LIVER ABSCESS: Focal suppurative inflammation of the liver. May be pylephlebitis due to ascending infection that
enters the liver through the portal veins, or cholangitis, if the infection had reached the liver through the bile ducts.
HEPATITIS:
A) HEPATITIS-A (HAV): Enterovirus-72
1) EPIDEMIOLOGY: Prevalent in underdeveloped countries due to mode of transmission.
TRANSMISSION: Fecal-oral. Found in shellfish, where viral particles can become concentrated.
It is not sexually transmitted, whereas both HAV and HCV are.
2) CLINICAL: As opposed to HBV and HCV, HAV is only acute -- there is no persistent infection.
Anicteric: Children with HAV usually do not present with jaundice. The disease may be silent. Adults, on the other hand, usually do have jaundice.
Recovery: Less than 1% of people with HAV get fulminant hepatitis and die. Most people recover.
3) DIAGNOSIS:
25-28 day incubation period.
Period of highest infectivity: then there is lots of virus in the feces -- before the patient becomes symptomatic.
Then, Anti-HAV IgM will appear in blood. Around the same time, AST and ALT will be high.
Then (5 -6 weeks later), IgM drops off and is replaced by IgG, which persists for life.
4) VACCINE: Available, and given to people traveling to endemic areas. Three doses.
HAV infection confers permanent immunity. There is only one serotype, and antibodies are protective.
Both passive immunity, and more recently, active immunization, is available.
B) HEPATITIS-B (HBV): Hepadnavirus
1) STRUCTURE:
Dane Particle: The entire infectious virion, including nucleocapsid, core antigens, and surface antigens.
HBV Surface Antigen (HBsAg): 4 phenotypes, useful for epidemiology: adw, ayw, adr, ayr.
2) EPIDEMIOLOGY: Sexual, fecal-oral, or intravenous or by exposure to blood products.
Due to multiple serotypes (a, d, y, w, r), the same person may be infected with HBV multiple times! However, simultaneous infection with multiple strains is common.
High incidence seen in SE Asia and Africa, corresponding to the incidence of hepatoma.
3) DIAGNOSIS:
| Term | Abbrev | Description |
| Hepatitis-B Surface Antigen | HBsAg | Surface antigen present on viral envelope. Its presence
indicates acute HBV infection.
Has serotype-makers: (1) a (always found), (2) d or y, and (3) w or r. |
| Antibodies to Hepatitis-B Surface Antigen | Anti-HBs | Antibodies to the surface antigen are not detectable during
acute infection even though they are being made, because
there is way more antigen and it sops it all up, making it
undetectable in the blood.
Presence of Anti-HBs indicates immunity to HBV or previous vaccination for HBV. |
| Hepatitis-B Core Antigen | HBcAg | Its presence indicates acute HBV infection, and signifies that the patient is currently infective. |
| Antibodies to Hepatitis-B Core | Anti-HBc | Its presence indicates acute or chronic HBV infection. Whether it is acute or chronic depends on whether IgM is present or IgG. |
| Hepatitis B e Antigen | HBeAg | This is the hepatitis viral polymerase and is present during acute infection. It indicates that the patient is currently infective. |
| Antibodies to Hepatitis-B e Antigen. | Anti-HBe | These aren't usually tested but are present during acute or chronic infection. |
| Antibodies to Hepatitis-A | Anti-HAV | Indicates acute infection of Hepatitis-A. There is no chronic Hepatitis-A infection. |
| Antibodies to Hepatitis-C | Anti-HCV | Indicates acute or chronic infection of Hepatitis-C. |
4) CLINICAL:
PROGRESSION:
HBsAg appears early on. Patient may have fever, malaise, jaundice, myalgia.
Window phase: Period after surface antigen disappears, but before antibody appears, during which patient may test negative for both!
Recovery: Anti-HBsAg antibodies are formed, indicating recovery from infection.
LAB:
Albumin would not be elevated and is not affected in the acute phase.
AST and ALT go sky high.
Both indirect and direct bilirubin will be elevated.
COMPLICATIONS:
Ag-Ab complex complications: Glomerulonephritis, arthritis, rash, vasculitis.
Chronic Hepatitis (either carrier, or chronic-active) occur in 5% of patients ------> further leads to cirrhosis
Fulminant Hepatitis also occurs, with rapidly progressing bad course. This has high mortality, but if patient recovers, they will not go into chronic hepatitis.
Hepatocellular Carcinoma risk is elevated, due to cirrhosis secondary to chronic hepatitis.
5) HEPATITIS-D (HDV): Hepatitis-B is required in order for this virus to infect. Can either be a co-infection, or it can be transmitted to a chronic HBV carrier.
EPIDEMIOLOGY: Prevalent in Mediterranean. In U.S., it is found mostly in IV at-risk groups: drug-users and hemophiliacs.
CLINICAL: Course is more severe and prognosis is poorer when Delta agent is present.
C) NON-A NON-B HEPATITIS:
1) HEPATITIS-C (HCV): Flavivirus
EPIDEMIOLOGY: Primary mode of transmission is parenteral route (blood). In the past has been associated with transfusions.
CLINICAL:
SYMPTOMS: Fever, malaise, flu-like symptoms, myalgia. Jaundice in 25%
AST and ALT levels may wildly fluctuate.
COMPLICATIONS: 50-70% progress to chronic liver disease. Many of those go on to develop cirrhosis.
2) HEPATITIS-E (HEV): Calicivirus
EPIDEMIOLOGY: Fecal-oral, often found in contaminated water. Found primarily in other countries -- India and central Asia.
CLINICAL: Acute infection similar to HAV.
High fatality rate among pregnant women, and high perinatal fatality.
3) HEPATITIS-G (HGV): Paramyxovirus
D) ACUTE VIRAL HEPATITIS:
1) PATHOLOGY:
Baloon hepatocytes can be seen.
Acidophilic Bodies can be seen.
2) CLINICAL:
AST, ALT will be extraordinarily high (5,000 - 10,000). If the patient has low or normal enzymes the next day, then that is bad! That means that there has been massive hepatic necrosis, and the liver cells are not producing the enzymes anymore.
E) CHRONIC HEPATITIS: The presence of inflammation and necrosis in the liver for more than 6 months.
1) PATHOLOGY: Chronic Persistent and Chronic Active are really just ends of a continuous spectrum.
CHRONIC PERSISTENT HEPATITIS: Milder form. Lymphocytic inflammation is limited to the portal tracts. "Asymptomatic Carrier" is the extreme mild end of the spectrum.
The Limiting Plate is still visible.
CHRONIC ACTIVE HEPATITIS: More severe. Necrotizing inflammation progresses to cirrhosis.
The Limiting Plate is impinged upon -- inflammatory cells destroy the limiting plate and invade the hepatic lobules themselves.
This form of infiltration results in piecemeal necrosis.
2) CLINICAL: Hepatosplenomegaly, jaundice, hepatic encephalopathy in severe cases.
F) AUTOIMMUNE HEPATITIS:
1) EPIDEMIOLOGY: Young and middle-aged women
2) PATHOGENESIS: Auto-immune SLE-like syndrome.
3) CLINICAL: Hypergammaglobulinemia, autoantibodies, positive LE-cell prep, are all found. Multisystem autoimmune involvement is typical (SLE-like syndromes).
TREATMENT = Corticosteroids. A favorable response is usually found.
G) CONFLUENT HEPATIC NECROSIS: Fulminant hepatitis, characterized by death of a large number of liver cells, or all liver cells. It affects whole lobules at a time. Three stages of severity:
1) Bridging Necrosis: Bands of necrosis stretch between adjacent portal tracts, or between adjacent central veins.
2) Submassive Confluent Necrosis: Necrosis of entire lobules or groups of adjacent lobules.
3) Massive Hepatic Necrosis: Soft, mottled parenchyma. Wrinkled capsule. Liver destroyed.
FATTY LIVER:
A) PATHOGENESIS: It can be caused by alcohol, Diabetes, obesity, drugs.
1) BIOCHEMISTRY: Alcohol increases lipolysis and delivery of free fatty acids to the liver. Fat metabolism in the liver decreases, while fat mobilization in the periphery increases.
Increased fat synthesis.
Decreased mitochondrial oxidation.
Impaired release of lipoproteins.
B) PATHOLOGY: Liver becomes big, yellow, and greasy. It is fully reversible.
ALCOHOLIC LIVER DISEASE:
A) PATHOGENESIS: Not all people who drink get alcoholic liver disease. There are genetic predisposing factors.
1) Alcohol Dehydrogenase metabolism results in toxic metabolites (formaldehyde) that can damage the liver.
2) There are also contributions from microsomal oxidases, peroxisomes, and catalases.
B) CLINICAL: DIFFERENTIAL DIAGNOSIS. Other diseases that resemble alcoholic liver disease
1) Steatonecrosis of liver caused by obesity.
2) Amiodarone = drug for cardiac arrhythmias is hepatotoxic.
3) Jejunoileal bypass can have complications similar to alcoholic liver.
4) Wilson's Disease
C) ALCOHOLIC HEPATITIS:
1) PATHOLOGY: Hepatic architecture remains basically intact, with isolated necrotic liver cells.
Necrosis of hepatocytes in the central zone.
Mallory Bodies: Hyaline inclusions are found in hepatocytes.
Neutrophilic infiltrate.
Central Hyaline Sclerosis: Collagen collects around the central venules. When it is extreme, it is called Central Hyaline Sclerosis, in which terminal venules are obliterated.
COUNCILMAN BODIES: Disparate dead hepatocytes. They are seen in alcoholic hepatitis and in viral hepatitis.
2) CLINICAL: Malaise, jaundice, RUQ pain
LABS: Leukocytosis, elevated AST.
D) ALCOHOLIC CIRRHOSIS: Micronodular cirrhosis.
CIRRHOSIS: The destruction of liver architecture. It is replaced by fibrous septa that contain islands of regenerating hepatocytes.
A) Morphological Classification:
1) MICRONODULAR CIRRHOSIS:
PATHOGENESIS: Most cases of cirrhosis, resulting from alcohol, Primary Biliary Cirrhosis, Hemachromatosis, Wilson's Disease.
PATHOLOGY: Uniform, small fibrous septa, surrounding inflammatory cells and hepatocytes.
2) MACRONODULAR CIRRHOSIS: Also called Post-Hepatic or Post-Necrotic Cirrhosis.
PATHOGENESIS: It occurs secondary to chronic active hepatitis.
Also, the micronodular pattern can be converted to the macronodular pattern by coalescence of micronodules.
PATHOLOGY: Large, irregular lobules surrounded by fibrous septa.
3) LABS:
Albumin is decreased (end-stage cirrhosis)
Gamma globulins are increased
Post-prandial chylomicrons are deficiency (exactly when they should be elevated).
B) PRIMARY BILIARY CIRRHOSIS: An autoimmune disease characterized by destruction of intrahepatic bile ducts and obstructive jaundice.
1) ETIOLOGY: Typically affects middle aged women.
2) PATHOGENESIS: Autoimmune; autosomal-recessive. They think that cytotoxic T-Cells attack the biliary epithelium.
Often associated with other autoimmune diseases, such as: Thyroiditis, rheumatoid arthritis, Sjögren Syndrome, SLE.
ANTIMITOCHONDRIAL ANTIBODIES are found in the serum of almost all patients.
Antinuclear Antibodies (ANA) and Anti Smooth Muscle antibodies may also be seen.
3) PATHOLOGY: Non-suppurative destruction of the intrahepatic bile ducts. Cirrhosis revolves around the portal triads. You would see bile lakes, just as in cholestasis. Four Stages, all of which can be present at the same time:
Duct Lesion: Non-Suppurative destruction of the bile-ductules. Mostly lymphocytic infiltrate.
Either no cholestasis or only central cholestasis may be present.
May see non-caseating granulomas in ductules or portal tracts.
Compensatory Ductule Proliferation: Bile ductule proliferation is seen in response.
Portal Fibrosis: Scarring leads to portal fibrosis and a paucity of bile ducts. Small bile ducts virtually disappear. Cholestasis may be severe and has moved to the periphery of the lobules.
Portal triads remain present but the ductules themselves are virtually obliterated.
Cirrhosis: End-stage liver. Green bile-stained gross appearance to liver.
4) CLINICAL: Female predominance,.
DIFFERENTIAL DIAGNOSIS: Primary Biliary Cirrhosis can be confused with other disease entities.
Primary Sclerosing Cholangitis: This is the easiest one to confuse it with. It affects bigger (more distal) segments of the bile ducts than PBC, and it has a slight male predominance.
Sarcoidosis: Granulomas in liver may be found.
Chronic Active Hepatitis: Look for destruction of bile ducts to distinguish them.
Drug-induced cholestasis.
LABS: High Alk.Phos. is characteristic. Bilirubin may be high or normal.
SYMPTOMS:
Intense Pruritus: Caused by retention of bile acids and bile salts.
XANTHOMAS: High Cholesterol is almost always seen, resulting in subcutaneous fatty lesions termed xanthomas.
Steatorrhea is seen due to no fat absorption, because of no bile secretion.
Vitamin-D deficiency (no absorption) ------> osteomalacia, osteoporosis.
Portal Hypertension.
5) TREATMENT: Methotrexate, or Liver Transplant. 5-yr survival at 65%
C) PRIMARY SCLEROSING CHOLANGITIS (SECONDARY CIRRHOSIS):
1) EPIDEMIOLOGY: Slight male predominance, as opposed to PBC which is female predominant. Can occur at any age, but under 45 is typical.
2) PATHOGENESIS: It is usually a partial idiopathic destruction of the extrahepatic bile ducts, causing bile backup. Cause of the inflammation is unknown.
40% of patients also have ulcerative colitis.
3) PATHOLOGY:
Onion-ring configuration around bile-ductules, followed by fibrosis.
4) CLINICAL: It causes obstructive jaundice and biliary cirrhosis.
SYMPTOMS: Fatigue, pruritus, jaundice, fever. Fever is more common with PSC than with PBC.
DIAGNOSIS: Endoscopic Retrograde Cholangiography (ERCP): Used for diagnosis. Inject dye into common bile duct to illuminate the biliary tree.
Normal = smooth ducts can be seen.
PSC: Rough edges are seen, along with areas of constriction followed by dilatation.
PROGNOSIS: Poor. Cholangiocarcinoma is a common complication.
D) SECONDARY BILIARY CIRRHOSIS (OTHER CAUSES): Extrahepatic biliary obstruction can be caused by many things:
1) Gallstones
2) Carcinoma of the head of the pancreas
3) Cancer of the Ampulla of Vater
4) Benign strictures
5) Congenital Biliary Atresia
E) HEREDITARY HEMOCHROMATOSIS (PRIMARY IRON OVERLOAD):
1) PATHOGENESIS: Idiopathic, congenital hyper-absorption of iron, and toxic accumulation of iron in liver and other organs.
2) PATHOLOGY:
Intense brown granules can be seen on trichrome stain.
Prussian Blue stain illuminates the iron.
The iron is usually found in the hepatocytes themselves.
3) SYMPTOMS: CLASSICAL SYMPTOM-CLUSTER
Cirrhosis: Iron-deposition in liver
Diabetes: Iron deposit in pancreas ------> damage to -cells.
Skin pigmentation
Cardiac failure.
4) SECONDARY IRON OVERLOAD: Iron accumulation by any other cause, such as increased dietary iron overload, thalassemia, anemias.
PATHOLOGY: Iron accumulates in Kupffer cells -- not the hepatocytes themselves.
F) WILSON DISEASE (Hepatolenticular Degeneration):
1) PATHOGENESIS: Autosomal-recessive deficiency of ceruloplasmin, leading to no way to transport copper in the blood ------> copper accumulates in liver.
Because it has no carrier protein, you also see a reduced amount of copper secretion in the bile, leading to yet more buildup of copper in blood.
Copper builds up in other organs, too: Brain, cornea, renal tubules.
2) PATHOLOGY: Resembles chronic active hepatitis.
It cannot be diagnosed as Wilson's Disease based on histology alone. It looks like chronic active hepatitis.
Copper Stain: Copper will appear as brown-granules in the hepatocytes.
3) CLINICAL:
Disease affects brain as well as liver, hence "Hepatolenticular Degeneration."
Kayser-Fleischer Ring: Seen in the eyes. The deposition of copper in Descemet's Membrane. Considered pathognomonic for Wilson's Disease.
TREATMENT: It can be treated by using chelating agents to sequester the extra copper.
G) CYSTIC FIBROSIS: Due to thick secretions in the bile, secondary biliary cirrhosis is found in 10% of patient who survive beyond 25 years.
H) 1-ANTITRYPSIN DEFICIENCY: An autosomal recessive disorder characterized by childhood cirrhosis and emphysema. AAT accumulates in liver cells in form of PAS positive globules.
1) PATHOGENESIS: 1-Antitrypsin is normally synthesized by liver. Failure of the liver to export the 1-Antitrypsin (due to the mutation) results in build-up of the Antitrypsin in hepatocytes, which leads to liver damage.
PHENOTYPES:
PI-MM: Normal wild-type 95%
PI-MZ: Heterozygote (deficient PI) 3-5%
PI-ZZ: Homozygote (no PI) <1% . Only the double-recessive allele is associated with liver damage.
2) CLINICAL: Can manifest in children or adults.
CHILDREN: Neonatal hepatitis, jaundice, paucity of bile ducts.
ADULT: Chronic active hepatitis, or cirrhosis.
DIAGNOSE: Measure 1-Antitrypsin blood levels to make diagnosis.
3) PATHOLOGY:
PAS-positive inclusions are seen in the cytoplasm of hepatocytes. These can be confused with Mallory Hyaline or with Councilman bodies. Use a PAS stain to differentiate them.
I) Inborn Errors of Carbohydrate Metabolism:
1) GLYCOGENOSIS TYPE IV (ANDERSON DISEASE): This is the only subtype of glycogenoses that is always complicated by cirrhosis.
It may occur in Glycogenosis Type III (Cori Disease), but it is not inevitable.
2) GALACTOSEMIA: Autosomal recessive deficiency of Galactose-1-Phosphate Uridyltransferase, which helps in converting galactose to glucose.
SYMPTOMS: Hepatomegaly, jaundice, hypoglycemia. Cataracts, mental retardation.
3) HEREDITARY FRUCTOSE INTOLERANCE: Deficiency of Fructose-1-Phosphate Aldolase. In infancy, buildup of fructose can lead to hepatomegaly, jaundice ------> progressive cirrhosis.
4) TYROSINEMIA:
HEPATIC FAILURE: The common endpoint to many liver diseases, and the clinical manifestations of cirrhosis. Presents with the following complications:
A) JAUNDICE: Build-up of direct and indirect bilirubin.
B) HEPATIC ENCEPHALOPATHY:
1) PATHOGENESIS: Caused by failure of liver to perform detoxification functions.
No urea cycle. The liver cannot make urea ------> build-up of ammonia.
Buildup of mercaptans.
Buildup of tryptophan, GABA, and benzodiazepines.
2) CLINICAL: Confusion ------> drowsiness ------> hepatic coma
ASTERIXIS: Flapping tremor of the hand that occurs when asked to dorsiflex the wrist.
C) HEPATORENAL SYNDROME: Renal failure often co-occurs. Cause unknown, but bile can be found in renal tubules.
D) COAGULOPATHY: No synthesis of clotting factors ------> easy bleeding, easy bruising.
1) Low platelet count (thrombocytopenia) ------> Splenomegaly, bone-marrow depression, DIC.
E) HYPOALBUMINEMIA: Leads to edema and ascites.
F) ENDOCRINE PROBLEMS: Caused by decreased hormone detoxification. Estrogen builds up as a result.
1) GYNECOMASTIA: Feminization due to excessive estrogen. Feminine body habitus.
2) SPIDER ANGIOMA: Usually in upper trunk and face.
3) PALMAR ERYTHEMA
G) PORTAL HYPERTENSION
PORTAL HYPERTENSION: Sustained increase in portal venous pressure, usually, but not always, due to cirrhosis.
A) INTRAHEPATIC PORTAL HYPERTENSION: Portal hypertension caused by intrinsic liver disease.
1) ALCOHOL is the most common cause.
2) Worldwide, Schistosomiasis is a common cause of intrahepatic portal hypertension.
B) PREHEPATIC PORTAL HYPERTENSION: Portal hypertension caused by an occlusion proximal to the portal tracts.
1) Portal Vein Thrombosis is most common cause.
2) Other causes: Tumors, hypercoagulability states.
C) POSTHEPATIC PORTAL HYPERTENSION: Portal hypertension caused by an occlusion anywhere beyond the liver lobules, either in the Central Veins or in the Hepatic Vein.
1) BUD-CHIARI SYNDROME: Occlusion of hepatic veins and venules, resulting in post-hepatic portal hypertension.
PATHOGENESIS: Often idiopathic, but it can be caused by polycythemia vera, primary and secondary liver cancers, oral contraceptives, trauma.
PATHOLOGY: Usually it is thrombosis of the larger hepatic veins that cause problems.
Centrizonal necrosis and fibrosis of central areas is seen, as central zone gets packed with backed-up blood.
Reverse Lobulation occurs, in which adjacent central zones join together, due to increased pressure, and are connected by fibrous septa.
Hepatic Veno-Occlusive Disease: A variant of Bud-Chiari, in which the smaller intrahepatic venules are occluded Crotalaria and Senecio plant alkaloids ("Bush Teas")
D) COMPLICATIONS:
1) PORTAL-CAVAL ANASTOMOSES: Blood is diverted to caval system due to back-up in the liver.
Esophageal Varices: Engorged veins around lower esophagus, which can rupture, causing surgical emergency.
Internal Hemorrhoids: Portal-caval anastomoses around the rectum.
Caput Medusae: Engorged umbilical veins, around the umbilicus.
2) Splenomegaly: Occurs due to increased blood pressure.
Hypersplenism is a decrease in the life-span of all blood-cells ------> enhanced removal of blood cells because of a hyperplastic spleen.
TOXIC LIVER INJURY:
A) ZONAL HEPATOCELLULAR NECROSIS: Predictable hepatotoxins typically cause centrilobular necrosis.
1) Examples of predictable hepatotoxins:
Yellow phosphorous
Phalloidin from mushroom Amanita Phalloides
Acetaminophen
Carbon Tetrachloride
2) PATHOLOGY: Coagulative necrosis, hydropic swelling, various amounts of fat.
B) FATTY LIVER: From drugs, it occurs in two predictable patterns.
1) MACROVESICULAR STEATOSIS: Large fat globules accumulate in the cytoplasm of liver cells.
Nucleus is pushed to the side.
2) MICROVESICULAR STEATOSIS: Smaller fat globules dispersed throughout. Usually associated with more severe liver disease. Nucleus retains its central position.
REYE'S SYNDROME: Example of microvesicular steatosis. Aspirin-induced toxicity after a febrile illness.
SYMPTOMS: Hepatic failure and encephalopathy.
C) INTRAHEPATIC CHOLESTASIS: A frequent complication of idiosyncratic hepatic drug reactions.
D) ACUTE VIRAL HEPATITIS: Morphologically, the idiosyncratic reactions of Isoniazid, Halothane, and Methyldopa are
indistinguishable from acute viral hepatitis.
NEONATAL HEPATITIS: In the neonate, prolonged cholestasis, morphologic evidence of liver injury, and inflammation. Multiple etiologies.
A) PATHOGENESIS
1) 1-Antitrypsin Deficiency: 30% of cases.
2) Infections: Viral hepatitis (HBV, HCV), TORCH Complex.
B) PATHOLOGY:
1) Giant-Cell transformation of hepatocytes is characteristic. Bile pigment prominent with hepatocytes.
C) BILIARY ATRESIA: Absence or hypoplasia of intrahepatic biliary tracts or the extrahepatic biliary ducts.
1) PATHOGENESIS: It either occurs secondary to or concurrent with neonatal hepatitis. It is thought to result from an inflammatory destructive process in the bile ductules.
D) CLINICAL: Neonatal hepatitis usually leads to full recovery. When it occurs with biliary atresia, it often leads to biliary cirrhosis, and the prognosis is much poorer.
1) KERNICTERUS: Permanent brain damage in cases of pro-longed hyperbilirubinemia, in neonatal hepatitis.
BENIGN NEOPLASMS:
E) HEPATIC ADENOMA: Benign tumors in women, occurring during reproductive years.
1) PATHOGENESIS: Oral Contraceptives are a well-known risk-factor.
2) PATHOLOGY: Solitary, sharply demarcated masses in liver. They are strictly benign and do not metastasize.
Tissue resembles normal liver tissue, except it is not arranged into lobules, and there are no portal tracts or central venules.
3) CLINICAL: Tumor can bleed into peritoneal cavity, in which case it is a surgical emergency.
F) FOCAL NODULAR HYPERPLASIA: Liver mass composed of fibrous septa and hepatocytic nodules.
1) PATHOLOGY: Center of mass contains a scar, from which the fibrous septa radiate.
G) HEMANGIOMA: Vascular tumor found in liver. Very common.
MALIGNANT NEOPLASMS:
A) HEPATOCELLULAR CARCINOMA: Primary Hepatocellular Carcinoma is also known as Hepatoma.
1) EPIDEMIOLOGY: Uncommon in U.S. Particularly common in sub-Saharan Africa, SE Asia, and Japan.
2) PATHOGENESIS:
Hepatitis-B, HBV is a causative factor. The genome of HBV is integrated into liver cells, in people with HBV infection who develop cancer.
Hepatitis-C, HCV also seems to be a causative factor.
Secondary cirrhosis from Hemachromatosis or 1-Antitrypsin deficiency is also a risk-factor.
3) PATHOLOGY: Soft and hemorrhagic tan masses in the liver. Multiple histologic types.
4) CLINICAL: Presents as a painful, enlarging mass in liver. Prognosis is dismal.
Complications: Peritoneal bleed, portal hypertension, cachexia, hepatic failure.
LANS: Increased -Fetoprotein (AFP) will be found. Also, the heptocellular tumors can secrete bile and mucin.
B) CHOLANGIOCARCINOMA: Malignant tumors of biliary epithelium, either intrahepatic or extrahepatic.
1) PATHOLOGY: Characteristic extensive fibrosis of bile ductules.
C) METASTATIC CANCER: As in the lung, the most common malignant tumors in the liver are metastases (at least in the U.S.)
1) They are also the most common cause of massive hepatomegaly.
2) CLINICAL: Weight loss is a common finding.
CHOLELITHIASIS: Gallstones
A) CHOLESTEROL GALLSTONES: Due to hypercholesterolemia.
1) PATHOGENESIS: Cholesterol is normally solubilized by a combination of bile acids and lecithin. Cholesterol stones can occur due to an excess of cholesterol or to a deficiency of bile acids, since bile acids solubilize the cholesterol. Either one can result in precipitation of cholesterol.
The LIVER is usually the culprit in the pathogenesis: hypercholesterolemia due to some reason, usually intrahepatic biliary obstruction or cirrhosis.
7-Hydroxylase Deficiency: Deficiency in enzyme required to make bile acids out of cholesterol ------> build-up of cholesterol and deficiency of bile acids ------> cholesterol stones.
Mucinous Glycoproteins from the liver are thought to serve as the nidus (seed) for the gallstone.
RISK-FACTORS:
Estrogen (oral contraceptives) results in increased secretion of cholesterol and may result in decreased production of bile salts.
Increased age
Obesity
Familial predisposition
2) PATHOLOGY: Yellow or tan. Size from 1 to 4 cm.
3) EPIDEMIOLOGY: Women are more likely than men to get during reproductive years.
B) PIGMENT GALLSTONES:
1) BLACK PIGMENT GALLSTONES: Due to precipitation of bilirubin in the bile.
PATHOGENESIS: Increased unconjugated bilirubin in the bile. Usually idiopathic.
Chronic hemolysis (hemolytic jaundice) can cause it.
2) BROWN PIGMENT GALLSTONES: Gallstones of calcium bilirubinate, intermixed with cholesterol and calcium soaps of fatty acids. Located more frequently in the bile ducts than in the gallbladder.
C) CLINICAL: Gallstones often remain silent until they cause obstruction.
1) Biliary Colic: Waxing and waning pain due to gallstones.
2) Acute cholecystitis may occur.
3) Choledocholithiasis: Gallstones passing into the common bile duct, where they cause obstruction.
4) Acute pancreatitis: May occur secondary to an obstructed bile duct.
5) Mucocele: Hydrops of the gallbladder occurring secondary to gallstones. It is a clear mucinous secreted by the gallbladder in a patient
with gallstones in the cystic duct.
CHOLECYSTITIS:
A) ACUTE CHOLECYSTITIS: Diffuse inflammation of gallbladder, usually secondary to gallbladder obstruction.
1) PATHOGENESIS: 95% associated with presence of gallstones.
2) PATHOLOGY: Moderate neutrophilic infiltrate, and focal ulcerations.
Widespread ulcerations is called "Gangrenous Cholecystitis."
3) CLINICAL
COMPLICATIONS:
Perforation ------> gallbladder contents spill, but are often contained by inflammatory adhesions.
Bile Peritonitis results if gallbladder contents escape the gallbladder region.
SYMPTOMS: Leukocytosis with left shift, fever, RUQ pain, shaking chills.
B) CHRONIC CHOLECYSTITIS: The most common disease of the gallbladder, associated with gallstones.
1) PATHOGENESIS: Repeated attacks of acute cholecystitis, or longstanding gallstones.
GALLBLADDER CANCER:
A) CARCINOMA of the GALLBLADDER:
1) PATHOGENESIS: Usually associated with gallstones or with chronic cholecystitis, thus it is more common in women than in men.
2) PATHOLOGY: Infiltrative, well-differentiated adenocarcinoma.
3) CLINICAL: 5-yr survival rate is less than 5%. The tumor does not become symptomatic until late stage.
B) CARCINOMA of the BILE DUCT and AMPULLA of VATER:
1) CLINICAL: You find obstructive jaundice relatively early, because of its location.
5-yr survival rate is thus much better, due to it becoming symptomatic earlier.
CONGENITAL DISORDERS:
A) ANNULAR PANCREAS: The duodenum is encircled by the pancreas.
PANCREATITIS:
A) ACUTE PANCREATITIS:
1) PATHOGENESIS: Autodigestion of pancreatic enzymes, resulting from a number of different causes. Most common causes are alcoholism, impacted gallstones and hyperlipidemia.
Obstruction: Impacted gallstones, carcinoma of the ampulla of vater, pancreatic carcinoma.
Alcoholism: Obscure pathogenesis, but extremely common.
Hyperlipidemia
Cholelithiasis
2) PATHOLOGY: Pancreatitis is non-infectious. It is strictly caused by autodigestion. It may, however, become secondarily infected.
Fat Necrosis: Digestion of pancreatic tissue leads to fat necrosis.
3) Two Subtypes:
ACUTE EDEMATOUS PANCREATITIS: Interstitial pancreatitis, most common and mildest form.
ACUTE HEMORRHAGIC PANCREATITIS: 5% of cases, very severe. Massive hemorrhage leads to quick death.
4) CLINICAL:
SYMPTOMS: Severe epigastric pain radiating to back.
Hypocalcemia: Fat Necrosis and autodigestion release fats into the blood ------> saponification of fats with calcium ------> hypocalcemia as all calcium is sequestered by fats.
Shock and superinfection, leading to sepsis.
Pulmonary and renal complications are both common and correlate with a bad prognosis.
Steatorrhea from fat malabsorption.
Pancreatic stones
Diabetes, from damage to islet cells.
DIAGNOSIS:
Amylase blood-levels go up in first 24 hrs (> 400 units)
Lipase levels will go up within 72-96 hours.
Enlarged pancreas by CT scan.
B) CHRONIC RELAPSING PANCREATITIS:
1) PATHOGENESIS: Repeated bouts of acute interstitial pancreatitis.
Alcoholism causes chronic pancreatitis.
Gallstones can cause chronic pancreatitis.
2) PATHOLOGY: Irregularly distributed fibrosis with decreased acinar tissue.
Calcification of pancreatic tissue is common. Ducts become hardened and form strictures, impeding flow. Calcification is visible on X-Ray.
Cysts: True cysts can form, with junk surrounded by fibrotic tissue.
PSEUDOCYST: Large spaces in pancreas filled with blood, exudate, pancreatic juices. The junk can become infected and form an abscess.
It is called a "pseudocyst" because it has no lining epithelium.
3) CLINICAL: Varied presentation, from colicky pain, to acute epigastric pain, to malabsorption.
Exocrine insufficiency
Steatorrhea
Weight loss
CYSTIC FIBROSIS:
A) PATHOGENESIS:
1) CFTR (CF Transmembrane Conductance Regulator): Faulty transporter
STRUCTURE: The protein consists of two transmembrane domains, two nucleotide-binding domains and a regulatory domain, containing protein kinase A and C phosphorylation sites.
F508 deletion of phenylalanine is 70% of cases and the most severe form of CF. There are other mutations that are less severe.
MECH: The F508 mutation results in defective processing of CFTR protein, which does not become fully glycosylated and is degraded before it reaches the cell surface.
2) Inadequate or no excretion of Cl- in glandular cells ------> little or no secretion of water ------> viscous mucous.
B) CLINICAL: Overall life expectancy of 24-25 years.
1) SYMPTOMS:
Chronic Pulmonary Disease ------> Bronchiectasis, widening and hypertrophy of bronchioles.
High risk for infection by Pseudomonas
Most common source of morbidity and mortality from CF in the young adult.
Pancreatic Insufficiency ------> Malabsorption
Pancreatitis results from plugged pancreatic ducts.
Endocrine pancreas usually is still okay.
Liver: Plugged mucous in biliary system can result in biliary cirrhosis and jaundice.
Meconium Ileus: Obstruction of the small bowel in the newborn. Caused by failure to pass meconium in neonate. Has been attributed to failure of pancreatic secretions to digest meconium.
This is the most common cause of death from CF in the newborn.
C) DIAGNOSIS: Sweat test
1) Sweat gland cell cannot reabsorb Cl- due to CFTR defect, therefore sweat is hypertonic rather than normal hypotonic.
D) EPIDEMIOLOGY: The most common lethal genetic disorder.
1) 1/2,500 get the disease.
2) 1/25 are heterozygous carriers.
EXOCRINE CANCERS of PANCREAS:
A) CYSTADENOMA: Large, benign, cystic tumor of pancreas, either of mucinous or serous types.
1) Mucinous Cystadenocarcinoma: A large multiloculated tumor lined by columnar mucin-producing epithelium in 40-60 year old women. It has a better prognosis of 40-90% survival rate if resected.
2) Serous Cystadenocarcinoma
B) PANCREATIC CARCINOMA: Very deadly cancer, due to its anatomic location.
1) EPIDEMIOLOGY: Tendency toward Native Americans, Hawaiians, New Zealanders.
2) PATHOGENESIS:
RISK-FACTORS: Smoking, Chemical Carcinogens, high-fat diet, Diabetes.
3) PATHOLOGY:
Anatomic Distribution:
Head: 60% of cancers and is more quickly diagnosed, because it causes biliary obstruction.
Tail / Body: 35%, insidious onset, late detection, and dissemination.
Desmoplastic Reaction: Formation of collagen around the tumor, due to reaction to secretory tumor cells.
Metastases go to liver, peritoneum, lungs, adrenals, bones.
4) CLINICAL:
SYMPTOMS: Weight loss, loss of appetite, gnawing epigastric pain, jaundice.
PROGNOSIS: Very grim prognosis, due to its anatomical location. Probably the worst prognosis of all cancers.
Courvoisier Sign: Obstruction of the common bile duct ------> acute painless dilatation of gallbladder, and jaundice.
Trousseau Sign: Increased risk for thromboembolism with pancreatic carcinoma. One fourth of patients will develop thromboembolism.
5) TREATMENT: Whipple Procedure. Surgery to remove the pancreas, duodenum, and a portion of the stomach. Operative mortality is
quite high.
ENDOCRINE CANCERS of PANCREAS: Islet-Cell Tumors
A) INSULINOMA: 75% of islet cell tumors. -Cell Tumor.
1) PATHOLOGY: Usually benign.
Hyperinsulinemia.
Serum proinsulin levels are also elevated.
2) CLINICAL: Whipple triad:
Hypoglycemic attack with serum glucose at 50 mg/dl
Symptoms of hypoglycemia -- CNS symptoms
Hypoglycemic attacks relieved by glucose intake.
B) GASTRINOMA (ZOLLINGER-ELLISON SYNDROME): 15-20% of islet cell tumors. G-Cell Tumor.
1) PATHOLOGY: Gastric hypersecretion leading to severe Peptic Ulcer Disease.
2/3 of tumors are malignant. They may occur in duodenum or pancreas, but not in stomach.
C) GLUCAGONOMA: 1-2% of islet cell tumors. -Cell Tumor.
1) SYMPTOMS: Triad of symptoms
Necrotizing migratory erythema
Diabetes
Anemia
D) SOMATOSTATINOMA: 1% of islet cell tumors. -Cell Tumor.
E) VIPOMA: 1-2% of islet cell tumors. VIP-secreting tumor.
1) Symptom Cluster:
Non-insulinoma tumor
Profuse watery diarrhea (10-20 gallon/day)
Hypokalemia and achlorhydria (WDHA syndrome)
F) PPOMA: 1% of islet cell tumors. Pancreatic Polypeptide-secreting tumor. Elevated pancreatic polypeptide in blood, with no specific symptoms.
G) MULTIPLE ENDOCRINE NEOPLASIA (MEN): Also called Multiple Endocrine Adenomatosis (MEA).
1) PATHOGENESIS: Autosomal dominant, with high degree of penetrance.
2) MEN TYPE I (WERMER SYNDROME): Cluster of findings
Gastrinoma ------> Peptic Ulcer
Prolactinoma ------> Hyperprolactinemia
Adrenal Cortical Adenoma
3) MEN TYPE II (SIPPLE SYNDROME): Cluster of findings
Bilateral Pheochromocytoma
No gastrinoma
Bilateral medullary carcinoma of the thyroid.
| Diabetes Type I (IDDM) | Diabetes Type II (NIDDM) | |
| Mechanism | Insulin is defective or is never formed. Antibodies against pancreatic -cells. | Insulin resistance; down-regulation of insulin receptors; failure of pancreas to release insulin even though it being formed. |
| Survival | Insulin is absolutely required for survival. | Patient will survive without insulin |
| Synonyms | Ketosis-Prone Diabetes
Juvenile-Onset Diabetes |
Ketosis-Resistant Diabetes
Adult-Onset Diabetes |
| Onset | Sudden, often discovered by ketoacidosis. Childhood polydipsia, polyphagia, polyuria. | Gradual, insidious. Often discovered incidentally, or when chronic complications arise. |
| Nutrition | Often thin. Failure of action of insulin. | Usually obese. |
| Ketoacidosis | Frequent | Seldom or never |
| Amyloidosis | Amyloidosis of Islets occurs | Amyloidosis does not occur. |
| Complications | Nephropathy is often cause of death
Microvascular disease does not show up until 20 or more years after diagnosis. |
Multiple causes of death
(atherosclerosis, nephropathy).
Microvascular atherosclerosis is present at time of diagnosis. |
| Epidemiology | 10% of cases. 50% concordance of disease between twins. | 90% of cases. Multifactorial inheritance. Diet with genetic predisposition. |
| Treatment (order of importance) | Insulin always required
Diet Never oral hypoglycemics |
Diet and exercise
Oral hypoglycemics Insulin |
TYPE-I DIABETES: IDDM
A) PATHOGENESIS: Few or no -cells, and little or no secretion of insulin.
1) Genetic predisposition. 50% concordance rate among twins.
2) Insulitis: Auto-immune attack against -cell is one of the mechanisms by which -cells are destroyed and insulin is deficient. Cause of auto-immune attack is unknown.
B) DIAGNOSIS:
1) In children, Classic symptoms:
Polydipsia
Polyphagia
Polyuria
2) Unequivocal elevation of plasma glucose > 200 mg/dl.
TYPE-II DIABETES: NIDDM
A) PATHOGENESIS: Multifactorial inheritance. Diet, environment, and genetic predisposition. Twins have 90% concordance rate for disease.
1) MECH: Insulin Resistance, caused by gross obesity. Defined as an insulin requirement of over 200 U per day for one week.
Both decreased receptor affinity and decreased receptor concentration contribute to insulin resistance.
Normal pancreas secretes 30-50 U insulin per day.
B) PATHOLOGY: Amyloidosis of islets is seen.
C) DIAGNOSIS: Two step process to establish diagnosis.
1) Fasting plasma glucose (FPG) > 140 mg/dl on two occasions.
2) Glucose Tolerance Test: Give oral glucose 75gm. Wait 2 hours and measure plasma glucose:
Failed Test: 2 hr plasma glucose > 200 mg/dl at least twice (1/2 hr intervals) during the two hour period.
Impaired Test: 2 hr plasma glucose > 140 mg/dl, with one intervening value >200 mg/dl after oral glucose tolerance test. About 25% of
patients of this condition eventually become diabetic.
COMPLICATIONS of DIABETES:
A) MECHANISMS:
1) GLYCOSYLATION of blood proteins
Examples of glycosylated proteins: hemoglobin, myosin in muscle, components of the lens, collagens, myelin.
Advanced glycosylation products are formed through time. The initial glycosylations are usually reversible.
Hemoglobin A1C (Hb-A1C): Glycosylated hemoglobin that is often measured to monitor the blood-sugar levels of diabetics.
2) POLYOL PATHWAY: The way to get rid of excess glucose in non-insulin-dependent tissues, such as the brain.
Glucose + NADH + N+ ------> Sorbitol + NAD+ (Aldolase Reductase).
Accumulation of Sorbitol is believed to play a role in Diabetic retinopathy, nephropathy, neuropathy, and microangiopathy.
B) ATHEROSCLEROSIS:
1) PATHOLOGY: Hyaline Arteriosclerosis. Pathogenesis uncertain.
2) CLINICAL: Major cause of death in older Type-II Diabetics.
Silent MI is common (50%) in this group because of accompanying diabetic neuropathy.
Coronary bypass is less effective in this group.
C) NEUROPATHY: Loss of touch, pain perception, and proprioception, particularly in extremities. Pathogenesis is complex.
1) FOOT PROBLEMS: They result from Neuropathy (they can't feel the sore), poor circulation (microvascular disease), and tendency to infection.
Greater than 50% of non-traumatic foot amputations occur in Diabetics.
D) RETINOPATHY: Microvascular disease of the eye. Neovascularization, and Retinopathy with macular sparing.
E) NEPHROPATHY:
1) INCIDENCE: It is more prevalent in Type-I Diabetes (50% of cases) than Type-II (10% of cases).
2) CLINICAL: Look for proteinuria, nephrotic syndrome and hypertension.
3) PATHOLOGY: A gradual increase in basement membrane (BM). After 10-20 years, material start to accumulate in mesangial zone ------> compromise vascular and urinary spaces.
Kimmelstiel-Wilson: Nodular glomerulosclerosis. Still the hallmark of diabetic nephropathy.
Papillary Necrosis can occur, as the renal pelvis can get infarcted due to microvascular disease (it is the least to receive blood supply in the kidney). Necrotic pelvis can be sluffed into the ureters and cause kidney stones.
F) INFECTIONS: Diabetics have depressed immunity and are prone to infection
1) Mucormycosis
2) UTI's
KETOACIDOSIS: Lack of insulin (i.e. high Glucagon:Insulin ratio) promotes lipolysis, breakdown of proteins, and glycogenolysis.
A) Coma: In hyperglycemia, high sorbitol in plasma ------> dehydration ------> coma.
1) Coma is more often seen with hypoglycemia than with hyperglycemia.
B) TREATMENT:
1) Crystalline Zinc Insulin is the most immediate-acting insulin, which is the treatment of choice for acute ketoacidosis.
2) Ketoacidosis is treated with both HCO3- (to relieve the acidosis) and K+ (to replace lost K+ in cells).
In Ketoacidosis, there is plenty of K+ in the blood, but the cells are starving for K+ because the patient is dehydrated.
When you give the IV insulin, glucose goes into cells, and K+ follows it. We therefore must replace this K+ to avoid hypokalemia.
C) BIOCHEMICAL CAUSE:
1) Glucagon promotes Lipolysis ------> lots of Acetyl-CoA in the blood.
Acetyl-CoA builds up in liver.
2) Glucagon promotes Gluconeogenesis ------> Oxaloacetate is diverted to work on making glucose and is therefore unavailable for the TCA cycle.
3) Excess Acetyl-CoA cannot be used in TCA cycle and is hence diverted to Ketone Body production.
HYPOGLYCEMIA:
A) SYMPTOMS: Palpitations, sweating, tachycardia, fainting, coma.
B) TREATMENT: IV-Glucose.
C) COMA: Hypoglycemic coma is more common in Diabetic than ketoacidosis coma, due to over treatment with insulin.
1) Give a comatose diabetic IV glucose, until their blood sugar is known for sure. If you give insulin to a hypoglycemic patient, you'll probably kill them!
D) ALCOHOL inhibits gluconeogenesis and thus can lead to hypoglycemia in Diabetics. Alcohol combined with insulin can lead to hypoglycemia.
E) SOMOGYI PHENOMENON: Paradoxical response to insulin, showing hyperglycemia and ketonuria because of exaggerated physiologic response to exogenous insulin.
1) PATHOGENESIS: Results from the release of catecholamine, cortisol, growth hormone and glucagon.
Type-I Diabetics are usually the people who exhibit this.
2) TREATMENT: You are giving them too much insulin for them to handle. Gradually decrease the amount of insulin by 10-20%.
INSULIN:
A) SYNTHESIS: Proinsulin is hydrolyzed to Insulin + C-Peptide
1) PRO-INSULIN: Consists of single-chain peptide (A and B chains and C-peptide).
2) C-PEPTIDE: Can be used in diagnosis of Diabetes.
Type-I Diabetics: It is completely absent due to no insulin synthesis.
Type-II Diabetics: It is normal or elevated.
B) SECRETION: Stimulated by Glucose, Vagal stimulation, and some amino acids. Mechanism involves a K+ channel and Ca+2 channel on the pancreatic -cell.
1) Fasting State: No glucose is around.
ATP is depleted.
K+ channels are open.
The cell is in the resting, hyperpolarized state.
2) Resting State: Plenty of glucose is around (or vagal stimulation).
ATP is plentiful.
The K+ channel closes.
The cell depolarizes.
Ca+2-channels open, Ca+2 flows in, and insulin is secreted.
3) Sulfonylureas: They promote insulin release by blocking the K+-channel, such that it is always closed. Hence the cell is depolarized and insulin is released.
C) INSULIN RECEPTOR: It's a Tyrosine Kinase.
1) STRUCTURE: A glycoprotein of 400 kDa consisting of four glycosylated peptide chains covalently linked by disulfide bonds. The molecules are each dimers, with and subunits.
-subunits (120 kDa): Include binding sites for insulin
-subunits (80 kDa): Involved in initiating some of the insulin actions.
2) Receptor-Affinity: In Scatchard plot, the negative slope of the line (Ke). Several things can decrease receptor affinity.
Glucocorticoid excess.
Insulin resistance due to anti-receptor antibodies.
Lipoatrophy: Loss of sub-cutaneous fat associated with insulin-resistant Diabetes.
3) Receptor Concentration: In Scatchard plot, the abscissa intercepts, R0. Can be decreased in several conditions:
Obese Type-II Diabetics: 10-20% decrease in insulin receptors is seen.
Acanthosis Nigricans: Velvety wart eruption, hyperpigmentation.
D) ACTION:
1) GLUCOSE-TRANSPORTERS: Insulin up-regulates the transport of GLUT4 transporters into the membranes of target cells.
2) LIVER:
Insulin promotes glycogenesis
Insulin antagonizes glucagonic effects of glycogenolysis, ketogenesis, and gluconeogenesis.
3) MUSCLE: Insulin promotes protein synthesis and glycogenesis.
4) FAT: Insulin promotes fat uptake and storage in adipocytes.
It stimulates lipoprotein lipase ------> free fatty acids from circulating lipoproteins.
Glucose transport and glycolysis generate glycerophosphate, which is needed as the glycerol backbone in triglyceride synthesis.
It inhibits intracellular lipase, preventing lipolysis in adipose tissue.
CYSTIC DISEASES OF THE KIDNEY:
A) CYSTIC RENAL DYSPLASIA: Not true dysplasia.
1) PATHOLOGY: Abnormal mesenchymal (rather than epithelial) tissue found in the neonatal kidney. It is found along with cysts of varying size.
You will see grossly dilated ureters, due to obstruction.
2) PATHOGENESIS: Congenital malformation, caused by obstructed urinary flow in utero. Proper urinary flow is necessary for the fetal kidney to develop properly.
Nephrons don't form properly, and not all glomeruli connect to their respective tubules. Blind (disconnected) tubules become cystic.
3) CLINICAL: Most common cause of an abdominal mass in the neonate.
Bad prognosis. Baby will die early, and presentation is similar to Potter's Syndrome (oligohydramnios).
Must distinguish it from a Wilms tumor. Inject a contrast-dye into large kidney to distinguish them.
If the dye distributes into cysts, then it is renal dysplasia. If it doesn't, then it is probably a solid Wilms tumor.
B) POLYCYSTIC KIDNEY DISEASE (PKD):
1) AUTOSOMAL DOMINANT PKD (ADPKD): A very common form of PKD that does not manifest until mid-adulthood.
PATHOLOGY: Formation of very large, disparate cysts.
Process can involve any part of the nephron.
CLINICAL: Renal failure occurs late-onset (adult) when it occurs, but it only occurs in about 50% of cases. The kidneys can withstand an incredible number of cysts before function is compromised.
SYMPTOMS:
Nocturia is a common early symptom, from Non-Oliguric failure.
Pain, due to bleeding infection, or rapid cyst growth.
DIAGNOSIS: CT-Scan is the best way to diagnose. Look for enlarged kidneys, cysts, or gross asymmetry between the two kidneys.
ASSOCIATED CONDITIONS
Liver Cysts are very common, about 50% of cases.
Berry Aneurysms: 10%
TREATMENT: These patients are often otherwise healthy and are ideal candidates for dialysis and/or transplantation.
In transplantation, the surgeons actually leave the old kidney in place!
PATHOGENESIS: Autosomal dominant. Penetrance of the disease is 100%. If you have the gene, you're sick.
2) AUTOSOMAL RECESSIVE PKD (ARPKD):
PATHOGENESIS:
PATHOLOGY: The cysts uniformly arise in the collecting ducts, rather than the whole nephron.
As compared to ADPKD, the cysts are diffuse and evenly distributed.
CLINICAL: Renal failure is virtually inevitable, usually occurring in childhood, but it can occur in adulthood.
ASSOCIATED CONDITION: Associated with congenital Hepatic Fibrosis.
3) ACQUIRED PKD:
PATHOGENESIS: Happens with renal failure patients on dialysis. The other kidney hypertrophies in response to unilateral kidney failure ------> healthy kidney hypertrophies ------> cysts form.
CLINICAL: COMPLICATIONS
Renal Cell Carcinoma is the most common complication. Renal tumors do not occur in the other forms of PKD.
If you were seeing anemia (due to renal failure) and you all of a sudden find a rising hematocrit, then suspect a renal cell carcinoma, secreting excess erythropoietin.
C) MEDULLARY SPONGE KIDNEY: Congenital sponge-like cysts formed in renal medulla. It does not become symptomatic unless and until patients present with renal stones late in life.
D) MEDULLARY CYSTIC DISEASE COMPLEX (Nephronophthisis): Also presents as cysts in the medulla, but this disease progresses to renal failure.
1) PATHOLOGY: Cysts around the corticomedullary junction, formed from the distal parts of nephrons.
2) CLINICAL: Patient presents with polyuric renal failure -- inability to concentrate urine.
Polyuria ------> JGA feedback shuts down glomerular filtration (the kidney thinks its peeing a lot do it inhibits filtration) ------> renal failure, uremia.
E) SIMPLE RENAL CYSTS: That's just what they are.
RENAL FAILURE:
A) GENERAL PROPERTIES:
1) High serum creatinine: Creatinine >> 1.0, indicating no glomerular filtration.
2) Azotemia: High BUN
3) Uremia: High frank urea in the blood, which can lead to encephalopathy in late stage.
4) Anemia: Anemia can occur due to no secretion of erythropoietin in damaged renal cells.
B) EPIDEMIOLOGY: Statistically, the most important causes of renal failure:
1) Autosomal Dominant PKD (high incidence)
2) Diabetes: due to both glomerulosclerosis and pyelonephritis.
Glomerulosclerosis is from Diabetic nephropathy
Chronic pyelonephritis results from recurrent UTI's (due to sweet urine, lost bladder motility)
Analgesic Nepropathy (interstitial nephritis due to phenacetin analgesics); very common.
C) ACUTE RENAL FAILURE: Most often occurs due to trauma, shock, or acute ischemia.
D) CHRONIC RENAL FAILURE: End-stage renal disease
NEPHROTIC SYNDROMES: Non-inflammatory nephropathies.
A) NEPHROSIS: Clinically characterized by proteinuria, loss of protein in the urine, usually due to loss of negative charge, or holes, in the glomerular basement membrane. Complications:
1) Hypoalbuminemia
2) Edema, resulting from hypoalbuminemia. Don't treat it with diuretics! It is not an inflammatory edema.
3) Hyperlipidemia, resulting from compensatory synthesis of lipoproteins in liver.
4) No hypertension.
B) MINIMAL CHANGE DISEASE (Epithelial Cell Disease): Loss of negative charge on glomerular basement membrane, leading to idiopathic proteinuria.
1) PATHOGENESIS: Loss of negative charge on glomerular basement membrane leads to loss of epithelial foot-processes, which is only visible at the EM microscopic level.
2) PATHOLOGY: The glomerulus appears histologically normal, but GBM appears flattened on EM.
Size normally is not a barrier to the passage of albumin through the GBM. Normally negative charge is the only barrier.
3) CLINICAL: The condition is not diagnosed until severe proteinuria (edema) occurs.
TREATMENT: Treatment with corticosteroids is always quite successful.
PROGRESSION: Minimal Change Disease never progresses to renal failure. If it does, then the diagnosis should be changed Focal Segmental Glomerulosclerosis.
C) FOCAL SEGMENTAL GLOMERULOSCLEROSIS: An extension of Minimal Change Disease, with same basic pathology.
1) PATHOGENESIS: Usually idiopathic, simply an extension of Minimal Change Disease with a worse prognosis. But, it can be caused by HIV or heroin.
HIV-Associated Glomerulosclerosis:
Heroin-Associated Glomerulosclerosis:
2) PATHOLOGY: In addition to loss of negative charge and flattening of epithelial foot-processes, we have:
Glomerular Sclerosis: Some Glomeruli are fibrotic, sclerosed, or totally obliterated. But, the damage is sparse:
"FOCAL": Only some nephrons are affected, whereas others are spared.
"SEGMENTAL": Only part of the glomerulus is affected. Half of the glomerulus may appear normal.
Hyalinosis: PAS-Positive material will appear in the affected glomeruli.
D) DIABETIC GLOMERULOSCLEROSIS (Kimmelstiel-Wilson Disease): Negative charge on GBM can be lost in Diabetes, too.
1) PATHOGENESIS:
Proteinuria: Glycosylation of GBM proteins causes loss of charge on GBM ------> proteinuria.
Progressive Renal Failure (lost filtration):
Mesangial Matrix (kidney macrophages) builds up, and mesangial cells do not turnover.
Microangiopathy: Capillary lumen become compromised as a result of mesangial cell buildup. Also, stuff builds up in the lumen itself.
Hyaline Arteriosclerosis: Uniquely, both the afferent and efferent arterioles can become atherosclerotic in Diabetes.
2) PATHOLOGY:
Thickened basement membrane.
3) CLINICAL: Proteinuria occurs before renal failure. Hematuria is rarely or never seen.
E) RENAL AMYLOIDOSIS: Accumulation of amyloid (crud) in the glomerular filter.
1) PATHOGENESIS: Amyloid builds up in capillary lumen, accumulates in GBM, and compromises filtration.
2) CLINICAL: Will see proteinuria early on, progressing to renal failure later.
DIAGNOSIS:
Congo-Red Stain will illuminate the amyloid and confirm Amyloidosis.
F) MEMBRANOUS NEPHROPATHY (Membranous Glomerulonephritis): It's commonly called glomerulonephritis, but it is non-inflammatory.
1) PATHOGENESIS: Immune Complexes accumulate in the glomerular basement membrane ------> nephrosis and proteinuria. Ag-Ab complexes can come from multiple sources:
Idiopathic (Idiopathic Membranous Nephropathy)
Endogenous Antigens: Tumor antigens (association with Colon Cancer), lupus nephritis (dsDNA antigen).
Exogenous Antigens: Hepatitis-B is a well-established viral antigen. Also certain drugs.
2) PATHOLOGY: The disease is classified as non-inflammatory, because there is no cellular proliferation, of mesangial cells or GBM epithelial cells.
Sub-epithelial humps: Immune-complexes create little spikes in the basement membrane, outpocketings of GBM.
Complement fixation does occur.
3) CLINICAL: Clinical course ranges from complete remission, to recurring proteinuria, to renal failure.
G) NON-INFLAMMATORY HEMATURIAS: Only two non-inflammatory conditions show any hematuria in the symptoms:
1) ALPORT SYNDROME (HEREDITARY NEPHRITIS):
PATHOGENESIS: Structural defect in Type-IV Collagen, leading to faulty glomerular basement membranes.
Weak basement membranes ------> capillaries leak ------> hematurias.
CLINICAL: Hematuria is common. Patient may also have auditory and ocular defects. Death from renal failure by age 40.
2) THIN BASEMENT MEMBRANE DISEASE (BENIGN FAMILIAL HEMATURIA): Idiopathic reduced thickness of basement membrane ------> recurrent hematuria.
SYMPTOMS: Patients will have recurrent hematuria in childhood or as young adults. They do not progress to renal failure.
NEPHRITIC SYNDROMES:
A) NEPHRITIS: Inflammatory disease of the glomerulus. General symptoms:
1) Hematuria
2) Oliguria. Inflammation and edema lead to impaired filtration.
3) Proteinuria
4) Hypertension results from impaired filtration. Note that there is no hypertension in the Nephrotic Syndrome.
B) DIFFUSE GLOMERULONEPHRITIS: Glomerulonephritis caused by general immune-mediated mechanisms (cell-mediated immunity and inflammation).
1) ACUTE (POST-INFECTIOUS) GLOMERULONEPHRITIS:
PATHOGENESIS: The glomerulonephritis is not caused by immune complexes themselves, although immune complexes are present. The disease-process is cell-mediated, caused by inflammatory cells.
Streptococcus Pyogenes is the classical organism that results in post-infectious glomerulonephritis.
Hepatitis-C (HCV) can also cause it.
PATHOLOGY:
Sub-epithelial, sub-endothelial, and mesangial deposits of immune complexes.
Inflammatory cells found within the glomeruli will release hydrolytic enzymes leading to rupture of capillaries and hematuria.
Variable deposition of immune complexes in GBM
CLINICAL: Hematuria is presenting symptom, along with flank pain.
DIAGNOSIS: Glomerulonephritis can be distinguished by other hematuria-presenting disease (prostatitis, cystitis, UTI), by the presence of red-cell casts in the urine.
By definition, the acute disease regresses by itself, leaving no permanent damage.
2) MESANGIAL PROLIFERATIVE GLOMERULONEPHRITIS: Not a distinct disease entity, but rather a morphological / pathological designation.
PATHOLOGY: An extension of glomerulonephritis, where mesangial cells proliferate in response to the inflammation.
Mesangial Cells: Resident macrophages in the kidney. They both contribute to and respond to glomerular inflammation.
Normal Functions:
They contract to open and close the capillary lumens of the glomerulus.
They serve as phagocytes and APC's, and have the same surface-markers as macrophages.
CLINICAL: This can be chronic, going on for years without progressing to renal failure.
3) MEMBRANOUS PROLIFERATIVE GLOMERULONEPHRITIS: Not a disease entity, but rather a morphological designation.
PATHOGENESIS:
Immune deposits get under the endothelium, and inflammatory cells proliferate and cause the endothelial layer to swell.
Endothelial cells synthesize more BM in response ------> thickened BM on top of the edema ------> lost filtration.
PATHOLOGY: Severe extension of glomerulonephritis, where both mesangial cells and capillary endothelial cells proliferate in response to glomerular inflammation.
Basement membrane thickening
Prominent hypercellularity of glomerulus
Mesangial cell proliferation.
Capillary lumen can become occluded by membrane and mesangial proliferation ------> renal failure.
CLINICAL: Patients with this severe of disease progress to renal failure regardless of treatment.
C) FOCAL GLOMERULONEPHRITIS: Glomerulonephritis caused by specific etiologies and disease processes.
1) SLE NEPHRITIS: Renal disease (Nephrosis) caused by Lupus ranges from mild to severe.
PATHOLOGY: Anti-dsDNA immune-complex deposition in many tissues.
Hematoxylin bodies are light microscopic entities that are considered pathognomonic for Lupus.
CLINICAL: As classified by WHO, five classes of renal disease in SLE:
CLASS I: Histologically normal, but immune complexes would still be found on EM.
CLASS II: Purely mesangial. Immune complexes confined to mesangial areas.
CLASS III: Focal and segmental glomerulosclerosis. Lesions involves capillaries.
By definition, less than 50% of glomeruli are involved.
CLASS IV: Diffuse proliferative glomerulonephritis. The worst category. More than 50% of glomeruli involved, with rapidly worsening course.
CLASS V: Diffuse Membranous Nephropathy. Carries a good prognosis. Non-inflammatory Nephrotic Syndrome, with appearance similar to that of Membranous Nephropathy.
Thick wire loop capillaries are the characteristic finding of SLE nephropathy Type V.
2) BERGER DISEASE (IgA NEPHROPATHY):
EPIDEMIOLOGY: Men, peak age at 30. Predominant in SE Asia. Also seen in U.S.
PATHOGENESIS: Unknown pathogenesis. Must have genetic predisposition, and it is associated with liver disease.
PATHOLOGY: Mild inflammation, IgA deposits in basement membrane. Inflammation is usually focal and segmental.
Inflammation is restricted to mesangium, hence it would be classified as a Mesangioproliferative Glomerulonephritis.
CLINICAL: Patient tends to get recurrent bouts of hematuria, even after a mild infection like a cold. Anything that kicks up the levels of IgA will result in hematuria.
PROGNOSIS is variable. 20% develop renal failure within 40 years.
3) HENOCH-SCHONLEIN PURPURA: Pathogenesis is identical to IgA Nephropathy in the kidney, but systemic manifestations differ.
CLINICAL: SYSTEMIC MANIFESTATIONS
Purpura of lower extremities
Polyarthralgia
Colicky abdominal pain, and bloody stools.
4) BACTERIAL ENDOCARDITIS: Glomerulonephritis is a complication of subacute bacterial endocarditis, of Staph Aureus or Strep Pyogenes origin. Clinical severity is variable.
D) CRESCENTIC GLOMERULONEPHRITIS: Morphological term for very severe glomerulonephritis.
1) PATHOLOGY: Crescents are formed as a regenerative mechanism, when whole glomeruli are destroyed and capillaries are ruptured.
2) PATHOGENESIS: May be found occurring with several disease entities:
Idiopathic: Pauci-Immune Glomerulonephritis
Wegener's Granulomatosis: Anti-Neutrophilic Cytoplasmic Antibodies (ANCA) will be found.
Goodpasture's Syndrome
3) GOODPASTURE SYNDROME (Anti Glomerular Basement Membrane Antibody Disease):
PATHOGENESIS: Auto-antibodies against the glomerular basement membrane (Type-IV collagen). Technically, it is called "Goodpasture Syndrome" when both the lungs and kidney is involved.
CLINICAL: Severe, crescentic glomerulonephritis.
TUBULOINTERSTITIAL DISEASES:
A) PYELONEPHRITIS:
1) PATHOGENESIS: Several factors predispose to an ascending infection of urinary tract.
Increased Residual Urine: BPH, urinary obstruction, lost urinary motility due to Diabetes, all make it so that the bladder doesn't completely empty on micturition. The remaining urine collect bacteria and can seed infection.
Bladder Reflux: Abnormally short, perpendicular entrance of the ureter into the bladder wall.
NORMAL: Ureter enters at an elongated, oblique angle. Pressure of micturition closes off the ureteral entrance, preventing backflow of urine.
SHORT INTRAVESICAL URETER: Ureter entrance is perpendicular. Pressure of micturition tends to make urine reflux back into the ureters, causing infection.
Interstitial Infection: Bacteria tend to infect the upper and lower poles of the kidney, because that is where the renal papillae are compound, flattened, and therefore receptive to infection by bacteria.
Renal Papillae in the center of the kidney tend to resist infection, due to shape of papillae.
2) PATHOLOGY: Acute, pyogenic (PMN) inflammation of renal pelvis and tubules.
3) CLINICAL: SYMPTOMS
Polyuria, due to inability to concentrate urine.
Flank pain, costovertebral angle tenderness
Hematuria
Leukocyte Casts in urine indicates that the infection has ascended to the tubules, rather than just remaining in the lower urinary tract.
4) CHRONIC PYELONEPHRITIS: Longstanding pyelonephritis leads to end-stage kidney, a shrunken, fibrotic kidney that cannot maintain renal function.
B) ACUTE TUBULAR NECROSIS (ATN): Acute damage to the tubules, from drugs (hypersensitivity), chemical toxicity, or ischemia.
1) PATHOGENESIS: ATN is not an inflammatory process, but is rather due to ischemia.
Prerenal: Fall in renal blood flow, from hypotension or shock.
Intrarenal: Toxic injury to any part of the kidney nephrons, from glomerulus to collecting ducts.
Postrenal: Due to urinary obstruction. To cause ATN, it must be a complete obstruction, i.e. involving both ureters or common urinary outflow.
2) ISCHEMIC ATN: Coagulation necrosis of renal tubules due to impaired blood flow or impaired filtration.
3) TOXIC ATN:
PATHOGENESIS:
Cisplatin = Chemotherapeutic drug is directly nephrotoxic.
Heavy metals, such as Mercury or Lead
Organic solvents
PATHOLOGY: Characteristic properties
"Distalization" of proximal tubules; loss of brush-border.
Single-cell necrosis of disparate cells
Granular casts
C) DRUG-INDUCED (ALLERGIC) ACUTE INTERSTITIAL NEPHRITIS: Dose-independent, immune-mediated hypersensitivity to a drug.
1) PATHOGENESIS: This is an inflammatory process, as opposed to ATN.
Lots of drugs can cause it, particularly NSAID's, sulfonamides, penicillins
2) ANALGESIC NEPHROPATHY: Chronic tubulointerstitial disease caused by analgesic drugs containing phenacetin.
CLINICAL: Common occurrence, and patients are at risk for developing Renal Cell Carcinoma.
D) MULTIPLE MYELOMA (Light-Chain Cast Nephropathy): In Multiple Myeloma, IgG light chains can get filtered and form casts in the renal tubules.
E) URATE NEPHROPATHY: Renal disease caused by deposition of urate crystals in renal tubules.
1) PATHOGENESIS: Anything causing increased Uric Acid in the blood.
Gout
Chemotherapy ------> higher DNA cell turnover rate ------> hyperuricemia
Leukemia and polycythemia similarly lead to hyperuricemia due to increased cell turnover rate.
RENAL VASCULAR DISEASES:
A) BENIGN NEPHROSCLEROSIS: It is not always benign and can lead to end-stage renal disease.
1) PATHOGENESIS: Renal Artery Atherosclerosis is the most common cause.
Renal Artery Atherosclerosis ------> tubular injury due to ischemia.
2) PATHOLOGY: Ischemia leads to tubular necrosis and fibrosis. Affected kidney is small and fibrotic.
It may happen that the other (non-affected) kidney is smaller. This can happen when the Renin-Angiotensin system kicks in to compensate for the ischemic kidney. Then, the other kidney can't handle the increased load and becomes necrotic.
3) HYPERTENSIVE RENAL DISEASE: Benign nephrosclerosis occurring in conjunction with hypertension.
B) MALIGNANT NEPHROSCLEROSIS (HYPERTENSION): The renal arterial changes occurring with Malignant Hypertension.
1) PATHOGENESIS: Diastolic blood pressure is at or above 125 usually.
2) PATHOLOGY:
Fibrinoid necrosis of the renal arterioles and the glomeruli.
3) CLINICAL: Hematuria and Proteinuria. Retinal changes, papilledema, headache, possible cerebral aneurysm are co-findings.
C) RENAL VASCULITIS: Renal vascular damage due to any of a number of vasculitides: Polyarteritis Nodosa, Wegener's Granulomatosis, Hypersensitivity Vasculitis.
D) THROMBOTIC MICROANGIOPATHY: Presence of thrombi in the renal vasculature.
1) HEMOLYTIC UREMIC SYNDROME (HUS): E.Coli bad strains. Symptom Cluster:
Acute Renal Failure
Thrombocytopenia
Hemolytic Anemia
2) THROMBOTIC THROMBOCYTOPENIC PURPURA: Similar to HUS, but more severe and with a worse prognosis.
General Properties:
It occurs in older people
The kidney is involved to a lesser extent than in HUS
It affects many organs
E) SCLERODERMA:
F) RENOVASCULAR HYPERTENSION: Hypertension caused by renal vascular stenosis ------> increased renin. Treatable by impeding the Renin-Angiotensin system, or by fixing the stenotic vessel(s).
G) BILATERAL CORTICAL NECROSIS:
UROLITHIASIS (RENAL STONES):
A) PATHOGENESIS: More common in men than in women. Multiple causes:
1) Calcium Stones: most common. Can occur from hypercalcemia which leads to hypercalcuria. There is also idiopathic hypercalcuria in which high urine calcium occurs without hypercalcemia.
2) Magnesium-Ammonium Phosphate: Can result from infection with urease(+) bacteria ------> alkaline urine ------> renal stones.
3) Urate Stones: Hyperuricemia ------> renal stones. Occur in 25% of patients with Gout.
B) CLINICAL: Stones may be asymptomatic, or can lead to severe hydronephrosis and pyelonephritis.
1) Renal Colic: Colicky (waxing and waning), excruciating flank pain of renal stones.
2) HYDRONEPHROSIS is the result of renal stones. Dilation of renal pelvis and calyces, and flattening of renal papillae.
RENAL CANCERS:
A) NEPHROBLASTOMA (WILMS TUMOR): Malignant, mixed tumor of young children, composed of mixed mesenchymal and epithelial tumor cells.
1) PATHOGENESIS: Wilms Tumor (WT) Gene is a Tumor-Suppressor gene, deleted in the case of Wilms Tumor.
2) PATHOLOGY: Tumor contains three different elements:
Metanephric blastema
Immature epithelial elements.
Immature mesenchymal tissue (stroma)
3) CLINICAL: Child presents with large abdominal mass. Treat with chemotherapy and surgical resection. Survival rate is good for young (< 2 yrs) children.
B) RENAL CELL CARCINOMA: Malignant tumor of renal tubular epithelial cells.
1) PATHOGENESIS:
RISK FACTORS
Cigarette smoking
Obesity, particularly in women.
ASSOCIATED CONDITIONS:
Analgesic Nephropathy
Von-Hippel Lindau Disease
2) PATHOLOGY: Uniform renal cells displaying clear cytoplasm. Yellow fleshy tumor on gross.
3) CLINICAL: Metastases is common. Tumor cells may become secretory.
SYMPTOMS: Hematuria, flank pain, palpable mass
Excessive erythropoietin ------> Polycythemia
Paraneoplastic Syndromes are common.
II/RENAL FAILURE
! Sudden loss of the kidney ability to maintain normal physiologic environment.
! oliguria, anuria, increased in BUN or serum CREATININE.
! LESS COMMONLY BE MANIFEST BY ENCEPHALOPATHY, VOLUME OVERLOAD, PERICARDITIS - BLEEDING - ANEMIA - HYPERKALIEMIA - HYPERPHOSPHATEMIA - HYPOCALCEMIA AND METABOLIC ACIDEMIA
SEPSIS IS A MAJOR CAUSE OF THE DEATH IN RENAL FAILURE
PROGRESSIVE HYPONATREMIA -HYPERKALIEMIA -AZOTEMIA - ACIDOSIS.
PATHOPHYSIOLOGY OF ATN :
VASCULAR EFFECTS: ***DECREASE RENAL FLOW
***DECREASED IN PERMEABILITY [Kf]
TUBULAR EFFECTS: ***OBSTRUCTION - TUBULAR BLOCKAGE
***BACK LEAK - BACK DIFFUSION
CLINICAL COURSE OF ATN:
***OLIGURIC PHASE OR ANURIC PHASE OR NON OLIGURIC ATN.
***DIURETIC PHASE
***RECOVERY PHASE
PATHOLOGY FINDING IN ACUTE TUBULAR NECROSIS:
BLOOD ANALYSIS SHOWS:
***INCREASE: BLOOD UREA NITROGEN [BUN]
CREATININE
POTASSIUM
PHOSPHATE
***DECREASE: HEMATOCRITS
URINARY INDICES IN ACUTE RENAL FAILURE:
INVESTIGATION OF RENAL FUNCTION:
***URINALYSIS
***BLOOD TESTS - BUN - CREATININE
CAUSES:
! PRERENAL
! INTRINSIC RENAL
! POST RENAL
| PRERENAL AZOTEMIA | POST RENAL AZOTEMIA[OBSTRUCTION UROPATHY] | RENAL ATM | GLOMERULONEPHRITIS |
=U/P>1.5
FeNA=[U/P NA]/U/P
Cr]]<0.01
|
|
|
|
! DIARRHEA
! DIURESIS
! GI HEMORRHAGE
INADEQUATE CARDIAC OUT PUT
DECREASED CLEARENCE OF METABOLITES
: BUN-CREAT-UREMIC TOXINS.
VOLUME REDISTRIBUTION:
! THIRD SPACE FROM:
! CIRRHOSIS
! BURNS
! NEPHROTIC
SYNDROME
KIDNEY RETAIN SODIUM IN ATTEMPT TO
INCREASE CIRCULATING VOLUME [RENAL
PERFUSION]
BUN > 20:1
CAUSES:
***decreased albumin
***nephrotic syndrome
***catabolic states.
***shock
***hepatorenal syndrome [mortality >95%]
! RAPIDLY PROGRESSIVE
GLOMERULONEPHRITIS
! VASCULAR:
RENAL ARTERY OR VEIN THROMBOSIS
VASCULITIS
! TUBULOINTERSTITIAL [ATN MOST
COMMON]
ATN=ACUTE TUBULAR NECROSIS
RENAL TISSUE DAMAGE:
GLOMERULAR FILTRATION AND TUBULAR
FUNCTION ALMOST CEASE.
CAUSES:
! ISCHEMIA
! NEPHROTOXINS
! GLOMERULONEPHRITIS AND
VASCULITIS
! CATASTROPHIC OCCLUSION
MAJOR VESSELS. INCREASED TUBULAR PRESSURE WHICH
DECREASED GRF.
CAUSES:
! URETHRAL OBSTRUCTION [MOST
COMMON]
! OBSTRUCTUCTION OF SOLITARY
KIDNEY
! BILATERAL URETRAL
OBSTRUCTION [LEAST COMMON]
! EXTRA RENAL OBSTRUCTION:
UROPATHY SECONDARY TO: ***PROSTATE
CANCER
***BENIGN PROSTATIC HYPERTROPHY
***RENAL CALCULI OCCLUSION OF THE
BLADDER OUTLET
INTRARENAL
DIAG:
! URETRAL OBSTRUCTION:
BLADDER CATHERIZATION
! URETHRAL OBSTRUCTION:
IMAGING OF RENAL CALYCEAL SYSTEM
BY ULTRASOUND OR RETROGRADE
PYELOGRAPHY.
! SUSPECT OBSTRUCTION WITH
ANURIA OR MARKED VARIABLE URINE
VOLUME.
Physical examination:
Prerenal azotemia:Impaired cardiac output: ***neck vein distention ***pulmonary rales ***pedal edema
volume depletion is suggested by :
***orthostatic blood pressure changes
***weight loss
***low urine output.
! URINE OUTPUT <400 ML/24H
! ELEVATED BUN AND CREATININE
! DECREASED CREATININE CLEARANCE
! A PROGRESSIVE DAILY INCREASE IN SERUM CREATININE IS DIAGNOSTIC OF ACUTE RENAL FAILURE
INTRARENAL INSULT:
ACUTE TUBULAR NECROSIS : ATN: THE MOST COMMON INTRINSIC RENAL DISEASE LEADING TO ARF.
PROGRESSIVE HYPONATRIEMA - HYPERKALIEMIA - AZOTEMIA - ACIDOSIS.
CAUSE: ***ISCHEMIC : SHOCK -SEPSIS -HYPOXIA - HYPOTENSION.
***TOXIC: RADIOLOGIC CONTRAST MEDIA
HEAVY METALS
AMINOGLYCOSIDES
MYOGLOBINURIA [BURNS , TRAUMA, POLYMYOSIS]
URINALYSIS => RENAL EPITHELIA CELLS , CELLULAR CASTS
! NEPHROTOXIC AGENTS: ***AMINOGLYCOSIDES
EXOGENOUS NEPHROTOXINS ***HEAVY METAL
***RADIOCONTRAST MEDIA
***ETHYLEN GLYCOL
ENDOGENOUS NEPHROTOXINS: ***INTRATUBULAR PIGMENTS [HEMOGLOBINURIA]
***INTRATUBULAR PROTEINS [MYELOMA]
***INTRATUBULAR CRYSTALS [URIC ACID, OXALATE]
! ACUTE INTERSTITIAL NEPHRITIS [AIN]:
ALLERGIC REACTION SECONDARY TO DRUGS [NSAIDSs, BETA LACTAMS]
! ARTERIOLAR INJURY:
***HTA
***VASCULITIS
***MICROANGIOPATHIC DISORDERS.
! GLOMERULONEPHRITIS:
SECONDARY TO IMMUNOLOGICALLY MEDIATED INFLAMMATION.
=========================================================
PRERENAL
RENAL
POSTRENAL
VOLUME DEPLETION:
GLOMERULAR:
OBSTRUCTION OF THE URINARY TRACT
FROM PROSTATE DISEASE, OR
RETROPERITONEAL DISEASE.
Pre renal
Acute intrinsic renal RBF
decreased
Much decreased GRF
Midly decreased
=0 URINE OUT PUT
Decreased to+/-400ml
Decreased to <400 BUN/Cr
INCREASED
RATIO>10/l
Increased ratio 10/l URINALYSIS
BENIGN
Increased tubular cells
and formed element URINE NA
<20 MEQ/L
>40 meq/l URINE OSM
>500 mosm/L
300mosm/l U/P CREAT RATIO
>40/l
<20/1 Fractional excretion
>1
>2 Duration
Transient
10-14 days Response to volume of
diuretics
Respond to volume
and/or diuretics
No response
TYPICAL CLINICAL PHASES OF ARF
DIAG:
***URINALYSIS: [PRONOSTIC AND DIAGNOSTIC INFORMATION]
***DISTPICK FINDINGS: POSITIVE FOR PROTEINS[3+,4+]=è INTRINSIC RENAL DISEASE WITH GLOMERULAR
DAMAGE.
PROTEIN TRACE , 2+: -PRERENAL AZOTEMIA
-OBSTRUCTION
-ACUTE TUBULAR NECROSIS
IN 24 H URINE IF THERE IS GREATER THAN 3GM OF PROTEIN, A GLOMERULAR RATHER THAN A VASCULAR OR
INTERSTITIAL PROCESS IS MOST LIKELY.
HYALIN CASTS: SEEN WITH :
-DEHYDRATATION
-AFTER EXERCISE
-IN ASSOCIATION WITH GLOMERULAR PROTEINURIA
RED CELL CASTS= -GLOMERULAR HEMATURIA
-GLOMERULONEPHRITIS
WHITE CELL CASTS= -RENAL PARENCHYMAL INFLAMMATION
GRANULAR CASTS =CELLULAR REMNANTS AND DEBRIS.
FATTY CASTS -HEAVY PROTEINURIA
-NEPHROTIC SYNDROME
RBC'S AND RED CELL CASTS=GLOMERULAR LESION
EOSINOPHILS IN A WRIGHT-STAINED URINE SEDIMENT = DRUG INDUCED ACUTE
INTERSTITIAL NEPHRITIS. ANATOMIC URINARY PROTEINURIA : SPECIFIC
2.ACUTE
TUBULAR
3.ACUTE
INTERSTITIAL
NEPHRITIS WBC'S WITH
CASTS
GRANULAR
CASTS
FATTY CASTS
RENAL
TUBULAR CELLS
RENAL TUBULAR
CELL CASTS
COURSE
GRANULAR AND
PIGMENTED
GRANULAR
CASTS
RBC'S,WBC'S,WBC CASTS,
GRANULAR
CASTS, RENAL
TUBULAR CELLS ++
++ 1010
1012
1010
1012 LATER 1010-1012
BUN>20 è PRERENAL AZOTEMIA
>500 =PRERENAL AZOTEMIA
300-350=ATN
CASTS ARE FORMED FROM URINARY TAMM-HORSFALL PROTEIN
PRODUCT OF THE TUBULAR EPITHELIAL CELLS.
WBC'S AND WHITE CELL CASTS =ACUTE INTERSTITIAL NEPHRITIS
ANATOMIC SITE
URINARY
SEDIMENT
PROTEINURIA
SPECIFIC
GRAVITY PRERENAL
TRACE
INCREASED INTRA RENAL
RBC'S WITH
CASTS
+++
INCREASED
POST RENAL
USUALLY
BENIGN URINE
SEDEMENT
TRACE
INCREASED
EARLY
: NLE=1200 MOSM/KG [INTACT TUBULAR SYSTEM]
Hypocalcemia:
Infection
MAJOR CAUSE OF DEATH:
INFECTION
INITIATING ILLNESS OR INSULT Treatment :
Reduction of Na+, K+, H2O and protein intake.
dialysis
Return to Table of Contents
Last Updated February 28, 1999 by Dr.Danil Hammoudi
Urinary finding in a 8 years old boy with anarsaca and a 24h
urine protein>3.5g =fatty casts.
ANTIANGINA THERAPY:
3 TRTS:
ORGANIC NITRATES
CALCIUM CHANAL BLOCKERS
BETA ADRENERGIC ANTAGONISTS
1. NITRATES ACTION:
GENERATION OF NO WHICH ACTIVATE GUANYLATE CYCLASE WHICH PRODUCE cGMP, WHICH CAUSE VASODILATION BY DECREASING
CALCIUM LEVEL IN THE CELL, PREVENTING THE CALCIUM -CALMODULIN COMPLEX FROM ACTIVATING MYOSIN LIGHT CHAIN
KINASE.
INHIBITION OF MYOSIN LIGHT CHAIN KINASE ===> DEPHOSPHORYLATION OF MYOSIN LIGHT CHAIN==> RELAXATION
DILATE LARGE EPICARDIAL VESSELS WITHOUT IMPAIRING AUTOREGULATION IN SMALL VESSELS===> INCREASES OXYGEN
DELIVRY TO THE ISCHEMIC MYOCARDIUM===> REDUCING PRELOAD ==> INCREASING PRESSURE GRADIENT FOR PERFUSION ACROSS
THE VENTRICULAR WALL ===> SUBENDOCARDIAL PERFUSION.
THERE IS NO INCREASE TOTAL CORONARY BLOOD FLOW IN PATIENT WITH ANGINA DUE TO ATHEROSCLEROSIS.
SIDE EFFECTS:
1. SEVERE HEADACHE
2. DIZZINESS
3. FLUSHING
4. SYNCOPE
5. REFLEX TACHYCARDIA
2. CALCIUM CHANNEL BLOCKERS:
NIFEDIPINE
VERAPAMIL
DILTIAZEM
1. MECHANISM:
BLOCK L-TYPE VOLTAGE SENSITIVE CALCIUM CHANNEL
IN THE SMOOTH MUSCLE : CA++BIND TO CALMODULIN ==> ACTIVATING MYOSIN KINASE==> PHOSPHORYLATION ==>
MUSCLE CONTRACTION BY DECREASING CALCIUM LEVELS IN THE VASCULAR SMOOTH MUSCLE
IN THE HEART : CALCIUM BINDING TROPONIN REMOVES
I/BUN
BLOOD UREA NITROGEN
Mesures urea nitrogen.
INFLUENCED BY VARIATIONS IN URINE FLOW RATE, AS WELL AS THE PRODUCTION AND METABOLISM OF
UREA.
Normal values:7-20 mg/dl.
The BUN/creatinine ratio often is used to differentiate prerenal, renal, postrenal [obstructive] azotemia.
Performed for : *Renal evaluation function.
*Liver disease.
*Dehydratation
Drugs that increase BUN:
! ALLUPIRINOL
! .AMINOGLYCOSIDES
! CEPHALOSPORINS
! CHLORAL HYDRATE
! CISPLATIN
! FUROSEMIDE
! GUANETIDINE
! INDOMETHACINE
! METHOTREXATE
! METHYLDOPA
! NEPHROTOXIC DRUGS [HIGH DOSE ASPIRIN, AMPHOTERICIN B, BACITRACIN, CARBAMAZEPINE,
COLISTIN, GENTAMICIN, METHICILIN, NEOMYCIN, PENICILLAMINE, POLYMYXIN B, PROBENICID,
VANCOMYCIN].
! PROPANOLOL
! RIFAMPIN
! SPIRINOLACTONE
! TETRACYCLINES
! THIAZIDE
! DIURETICS
! TRIAMTERENE.
Drugs decreasing BUN:
! CHLORAMPHENICOL
! STREPTOMYCIN
! MYOCARDIAL INFARCTION
! EXCESSIVE PROTEIN
CATABOLISM [STARVATION]
! EXCESSIVE PROTEIN
INGESTION
! GASTROINSTINAL BLEEDING
! HYPOVOLEMIA
[BURNS-DEHYDRATATION]
! RENAL DISEASE:
***GLOMERULONEPHRITIS
***PYELONEPHRITIS
***ACUTE TUBULAR NECROSIS
***RENAL FAILURE
***URINARY TRACT OBSTRUCTION
[TUMOR,STONES, PROSTATIC
HYPERTROPHY]
! SHOCK
! LOW PROTEIN DIET
! MALNUTRITION
! OVER HYDRATATION PATIENTS WITH LIVER DISEASE, THE BUN LEVEL MAY BE LOW EVEN IF THE KIDNEYS ARE NORMAL.
QuickView Table of Blood Urea Nitrogen (BUN)
Common Reference
Ranges Critical value Natural substance? Inherent activity? Location Major causes of ... After insult, time to
... Drugs often
monitored with test Causes of spurious
results
BUN/CREAT ELEVATED BY:
! DIET,
! TOTAL PARENTERAL NUTRITION,
! GLUCOCORTICOID THERAPY,
! NEOPLASMS AND ANTIBIOTICS,
! EXCESSIVE PROTEIN CATABOLISM
NORMAL IN RENAL AZOTEMIA
LOW RATIO:
! PREGNANCY,
! OVERHYDRATATION,
! SEVERE LIVER DISEASE,
! MALNUTRION
COMMON CAUSE OF PRERENAL AZOTEMIA:
! SHOCK
! ECF DEPLETION
! MASSIVE GI HEMORRHAGE
! SEVEREHEART AND LIVER FAILURE.
! BILATERAL TIGHT RENAL ARTERY STENOSIS. </COMMENT>BLOOD UREA NITROGEN - Blood urea nitrogen (BUN) is a metabolic by product ( in the liver) from the
breakdown of blood, muscle, and protein. Blood urea nitrogen can be measured from a simple venipuncture specimen. Abnormal
elevation in the blood urea nitrogen can indicate renal disease, dehydration, congestive heart failure, gastrointestinal bleeding,
starvation, shock, or urinary tract obstruction (by tumor or prostate gland). Low BUN level can indicate liver disease, malnutrition, or
a low protein diet. Normal BUN levels should be between 7 and 20 mg/dl (milligrams per deciliter).
Creatinine
1/creatinine
2/urine creatinine
3/urine clearence
ALL DETERMINE RENAL FUNCTION
1/CREATININE:
0.8 TO 1.4 mg /dl
Creatinine can be converted to ATP.
The filtered creatinine is not reabsorbed by the kidney tubules.
A small amount of creatinine is added to the urine by the process of tubular secretion.
The amount of creatinine excreted in the urine is primarily a function of glomerular filtration. .
Creatinine is excreted entirely by the kidney.
With normal renal excretory function, the serum creatinine level should remain constant and normal.
Drugs increasing cretinine:
! Aminoglycosides [ gentamicin]
! CIMETIDINE
! HEAVY METAL CHEMOTHERAPEUTIC [CISPLATIN
! NEPHROTOXIC DRUGS: CEPHALOSPORIN [CEFOXITIN]
DIABETIC NEPHROPAHY
ECLAMPSIA
GLOMERULONEPHRITIS
MUSCULAR DYSTROPHY
PRE-ECLAMPSIA
PYELONEPHRITIS
SHOCK
CONGESTIVE HEART FAILURE
RENAL FAILURE
RHABDOMYOLYSIS
URINARY TRACT OBSTRUCTION
RARE: ACROMEGALY
ACUTE TUBULAR NECROSIS
GIGANTISM MYASTHENIA GRAVIS Creatine clearence=GRF=GLOMERULAR FILTRATE RATE
Creatinine clearence is technically the amount of blood that is cleared of creatinine per time period [ml/min] =nl = 120 ml/min for an
adult[97-137 ml/m in male ,88-128 ml/min in female]= inversely related to serum creatinine.
If the clearence drop to one half of the old level===> serum creatinine doubles.
DECREASE WITH AGE [6.5 ml/min/1.73 m2]
The renal plasma clearance of any substance X is:
Cx =[UX ] [ VX]
PxT
Ux=concentration of x: mg/ml of urine
Vx=urine volume/min from 24h urine volume
Px= plasma concentration of x in mg/ml
Cx =volume of plasma cleared of substance x /min
t=time
ESTIMATED CREATINE CLEARENCE:
[140-AGE[YRS]][BODY WEIGHT [KG]]
72 [SERUM CREATININE [MG/DL]
FOR WOMEN MULTIPLY BY 0.85
THE CREATININE CLEARENCE NORMALLY DECREASES WITH AGE.
GRF DECREASED IN :
! acute tubular necrosis
! congestive heart failure
! dehydratation
! glomerulonephritis
! renal ischemia
! shock
! acute bilateral obstructive uropathy
! acute nephritic syndrome
! acute renal failure
! chronic renal failure
! end stage renal disease
! medullary cystic disease
! rapidly progressive [crescentic ] glomerulonephritis
! wilm=s tumor.
Drugs decreasing creatine clearence measurement:
! aminoglycosides
! cimetidine
! cisplatin
! cephalosporin [cefoxitin].
Drug increasing creatine clearence:
! diuretics
Factors controlling GRF:= STARLING=S FORCES:
! Size of the capillary bed
! Permeability of the capillary
! hydrostatic pressure gradients across the capillary wall
! osmotic pressure gradients across the capillary wall.
Excreted=filtered-reabsorbed+secreted
QuickView Table of Serum Creatinine (SCr)
Common Reference
Ranges Critical value Natural substance? Inherent activity? Location Major causes of ... After insult, time to
... Drugs often
monitored with test Causes of spurious
results 2/ urine creatinine::
0.0 - 2.5 g/24h
spot collection = 25-400 mg/dl
PROTEINURIA:
excretion of excessive amount >150mg/day
1/ benign proteinuria
2/pathologic proteinuria
3/ overload proteinuria
! ORTHOSTATIC PROTEINURIA
! PERSISTANT ASYMPTOMATIC
PROTEINURIA ! TUBERCULOINTERSTITIEL ***AMYLOIDOSIS
***LEUKEMIA
[MONOCYTIC,MONOMYELOCYTIC]
***MULTIPLE MYELOMA
***WALDENSTROM=S
MACROGLONUMINEMIA ! HEREDITARY
! NON
HEREDITARY
2/TUBULOINTERSTITIAL:
! HEREDITARY
! NON
HEREDITARY ! REPEATED
ALBUMIN OR BLOOD
TRANSFUSIONS
! RHABDOMYOLYSIS
[MOST COMMON CAUSE
OF PROTEINURIA IN
CHILDHOOD] ! CONGENITAL NEPHROTIC
SYNDROME
! ALPORT SYNDROME ! CYSTINOSIS
! GALACTOSEMIA
! LOWE SYNDROME
! MEDULLARY CYSTIC KIDNEY
! PROXIMAL RTA
! WILSON DISEASES 1/ ACUTE GLOMERULONEPHRITIS
[GN]
! POSTSTREPTOCOCCAL GN
! HEMOLYTIC UREMIC
SYNDROME
! HENOCH SCHOENLEIN
PURPURA
2/CHRONIC GN
A/PRIMARY GN
B/SECONDARY GN
NON HEREDITARY:
! ACUTE TUBULAR NECROSIS
! ANALGESIC ABUSE
! ANTIBIOTICS
! CYSTIC DISEASES
! HEAVY METAL POISONING
! HOMOGRAFT REJECTION
! HYPOKALIEMA
! INTERSTITIAL NEPHRITIS
! PENICILLAMINE
! REFLUX
PRIMARY GLOMERULONEPHRITISSECONDARY GLOMERULONEPHRITIS
! MINIMAL CHANGE DISEASE
! FOCAL SEGMENTAL GLOMERULOSCLEROSIS
! MESANGIOPROLIFERATIVE GN
! MEMBRANOUS GN
! MEMBRANOPROLIFERATIVE GN
! BERGER [IG A] GN
! GOODPASTURE NEPHROPATHY
! SLE NEPHROPATHY
! WEGENERS NEPHROPATHY
! DIABETIC NEPHROPATHY
! RENAL VEIN THROMBOSIS
! SICKLE CELL DISEASE
Return to Table of Contents
Last Updated February 28, 1999 by Dr.Danil Hammoudi
Clinical problems with acute renal failure
Uremia:
Increased BUN
Decreased BUN ! CONGESTIVE HEART FAILURE
! LIVER FAILURE
Parameter 1
Parameter 2
Description
Comments
Adults
8-20 mg/dL2.9-7.1
mmol/L
Pediatrics
4-20 mg/dL
< 1 year old
A. > 40 mg/dLB. >
100 mg/dLC. > 20
mg/dL increase in 24
h
A. Unexpected; no
dehydrationB. Risk of
uremiaC. Consistent
with new renal failure
Yes
Nitrogenous
end-product of protein
metabolism
No
No normal
physiologic activity
Production
Liver
From Ammonia and
CO2
Storage
Not stored
Secretion/excretion
Excreted unchanged
viaglomerular
filtration
Some secretion and
reabsorption
High results
Renal
dysfunctionDehydration and high-protein
diet
Table 1
Associated Signs &
Symptoms
Signs & Symptoms of
renal failure and
uremic syndrome
Decreasing urine
output, etc.
Low results
Hepatic
failurecachexia
Also overhydration
Associated Signs &
Symptoms
Signs & Symptoms of
underlying disorder
Does not cause signs
& symptoms directly
Initial elevation
6 - 12 hrs
Depends on cause
Peak values
6 hrs - 6 days
Assumes insult not
removed
Normalization
6 hrs - 6 days
Assumes insult
removed and no
permanent damage
Aminoglycosides,
Amphotericin B,
gallium, lithium,
diuretics
Table 3
Falsely Elevated
Chloral hydrate
Assay dependent
Falsely Lowered
Chloramphenicol and
streptomycin
Assay
dependentSodium
fluoride in collection
tube depresses results
of urease assays
</TBODY>
BUN/CREAT > 15 ==> PRERENAL - POST RENAL AZOTEMIA
INCREASED
DECREASED DEHYDRATATION
MUSCULAR DYSTROPHY [LATE
STAGE]
Parameter 1
Parameter 2
Description
Comments
Adults
0.7 - 1.5 mg/dL62
-133 mmol/L
Pediatrics
0.2 - 0.7 mg/dL18 -
62mmol/L
SCr (mg/dL) = height
(in) x 0.01
> 2 mg/dL or sudden
increase > 1 mg/dL
Yes
Waste product of
muscle metabolism
No
No physiological
activity
Production
Muscle
From creatine and
creatine phosphate
Storage
Not stored
Secretion/excretion
Excreted unchanged
viaglomerular
filtration
Some secretion
High results
Renal dysfunction
Tables 2-4
Associated Signs &
Symptoms
Signs & Symptoms of
renal failure
Decreasing urine
output, acid-base
imbalances, anemia
Low results
Abnormally low
muscle mass
Cachexia and chronic
neuromuscular disease
Associated Signs &
Symptoms
Causes of low muscle
mass
Does not cause signs
& symptoms directly
Initial elevation
6 - 24 hrs
Usual maximum
increase of 1-2
mg/dL/day
Peak values
3 - 6 days
Assumes insult not
removed
Normalization
3 - 6 days
Assumes insult
removed and no
permanent damage
Aminoglycosides,
Amphotericin B,
gallium, lithium,
diuretics
Table 3
Table 4
Assay dependent
</TBODY>
BENIGN
PROTEINURIA
PATHOLOGIC
PROTEINURIA
OVERLOAD
PROTEINURIA
! BENIGN
TRANSCIENT
PROTEINURIA
! GLOMERULAR
! NEOPLASTIC:
1/GLOMERULAR:
! IDDM
GLOMERULAR
TUBULOINTERSTITIAL HEREDITARY:
HEREDITARY:
NON HEREDITARY:
