Unit 9 Past Paper PDF

1 Diseases of the GI Tract, Liver, Gallbladder, and Pancreas PYLORIC STENOSIS Anatomically, the gastric outflow tract is obstructed by hyperplasia of the pyloric muscularis propria. Edema and inflammatory changes in the mucosa and submucosa may aggravate the nar...

1 Diseases of the GI Tract, Liver, Gallbladder, and Pancreas PYLORIC STENOSIS Anatomically, the gastric outflow tract is obstructed by hyperplasia of the pyloric muscularis propria. Edema and inflammatory changes in the mucosa and submucosa may aggravate the narrowing. Most common congenital form is congenital hypertrophic pyloric stenosis. 3-5 times more common in males and has an overall incidence of 1 per 300 to 900 live births Generally presents between the 3rd and 6th weeks of life as new-onset regurgitation, projectile nonbilious vomiting after feeding, and frequent demands for refeeding Physical examination reveals a firm, ovoid, 1- to 2-cm abdominal mass in up to 90% of cases Acquired pyloric stenosis occurs in adults as a consequence of antral gastritis or peptic ulcers close to the pylorus. Carcinomas of the distal stomach and pancreas may also narrow the pyloric channel due to fibrosis or malignant infiltration - Pyloric stenosis may be either congenital or acquired. The most common congenital form is congenital hypertrophic pyloric stenosis. HIRSCHSPRUNG DISEASE Patho: ○ Familial, congenital disorder of the large intestine in which the autonomic ganglia are reduced or absent ○ Occurs 1:5000 live births ○ Most commonly found in infants and children ○ Males more than females Clinical manifestations ○ Typically presents with a failure to pass meconium in the immediate postnatal period. ○ Profuse diarrhea, hypovolemic shock, intestinal perforation ○ Stasis of stool and megacolon may occur ○ Fecal stagnation; enterocolitis with bacterial overgrowth - Hirschsprung disease causes functional obstruction of the colon due to failure of ganglion cells to migrate to the wall of the colon resulting from a mutation in the receptor tyrosine kinase. REYE SYNDROME Primarily a disease of children Appears to involve mitochondrial injury in the setting of a viral illness. Aspirin may cause or perpetuate damage to cellular mitochondria resulting in the inhibition of fatty acid metabolism. The neurologic features likely result from hepatic mitochondrial dysfunction causing elevated ammonia levels. Hyperammonemia may induce astrocyte edema resulting in diffuse cerebral edema and subsequent elevated intracranial pressure. Pathology studies have revealed astrocyte edema, loss of neurons, fatty degeneration of kidneys, and a swollen and reduced number of mitochondria Stage 1: Persistent, copious vomiting, Lethargy, nightmares, increased somnolence, Confusion Stage 2: Stupor, disorientation, combativeness, delirium, Hyperreflexia, positive Babinski sign, lack of appropriate response to noxious stimuli, dilated and sluggish pupils, Hyperventilation, tachycardia Stage 3: Obtunded, comatose, decorticate rigidity Stage 4: Pupil dilation with minimal response to light or fixed and dilated pupils, deconjugate gaze with caloric stimuli, Deep coma with decerebrate rigidity Stage 5: Seizures, Flaccid paralysis, absent deep tendon reflexes, no pupillary response, Respiratory arrest, Death - Over the past 4 decades, the mortality rate of Reye syndrome has dropped from 60% to about 20%, chiefly due to early recognition and aggressive management. By preventing increased intracranial pressure and edema, death can be avoided in many children. For those who survive, full recovery has been noted in about two-thirds of patients. ESOPHAGEAL OBSTRUCTION: PATHO Primary function of the esophagus is to deliver ingested solid food and fluids to the stomach-can be impeded by physical or functional obstruction. The latter results from disruption of coordinated peristalsis after swallowing. Wall stress is increased; esophageal dysmotility may result in the development of small diverticula Mechanical obstruction caused by strictures or cancer typically presents as progressive dysphagia that begins with the inability to swallow solids. Benign esophageal stenosis is generally caused by fibrous thickening of the submucosa and is associated with atrophy of the muscularis propria and secondary epithelial damage Stenosis is most often due to inflammation and scarring that may be caused by chronic gastroesophageal reflux, irradiation, or caustic injury Patients with functional obstruction or benign strictures maintain their appetite and weight  2 Malignant strictures are often associated with weight loss. ESOPHAGEAL OBSTRUCTION Esophageal dysmotility falls into three principal patterns ○ Nutcracker esophagus An abnormality in which swallowing contractions are too powerful. In up to half of patients, this condition is caused by gastroesophageal reflux. Diffuse esophageal spasm ○ Also known as corkscrew esophagus due to the appearance of barium swallow, it is characterized by repetitive, simultaneous contractions of the distal esophageal smooth muscle. Unlike nutcracker esophagus, these contractions are of normal amplitude. Lower esophageal sphincter dysfunction ○ High resting pressure or incomplete relaxation, may be present as an isolated anomaly or accompany nutcracker esophagus or diffuse esophageal spasm MALLORY-WEISS SYNDROME Patho: Longitudinal tear in the mucosa or submucosa of the caria or lower portion of the esophagus near the gastroesophageal junction. ○ Primarily caused by prolonged or forceful vomiting in which the upper esophageal sphincter fails to relax during the vomiting process. Risk Factors: 75% are men who ingest excessive ETOH or salicylates. Other contributing factors are coughing, straining with BM, trauma, hiatal hernia, esophagitis, and gastritis. Clinical Manifestations: ○ Vomiting of blood and passing large amounts of blood rectally after vomiting episode. ○ Epigastric or back pain may also be present. INFECTIOUS ESOPHAGITIS Most often due to herpes simplex virus Infections are more common in patients who are debilitated or immunosuppressed May be caused by herpes simplex virus Cytomegalovirus (CMV) Fungal organisms - candidiasis is most common REFLUX ESOPHAGITIS (GERD) Patho: ○ Closure strength of the lower esophageal sphincter (LES) is adversely affected. Medications, fatty foods, caffeine, ETOH, smoking, sleep position, obesity, low acid. ○ Increased intraabdominal pressure (Pregnancy, ascites) Clinical Manifestations: ○ Severity of clinical manifestations depends on the frequency, duration, volume, and acidity of material being refluxed. ○ Heartburn, regurgitation, chest pain, dysphagia. Complications: ○ Reflux esophagitis – inflammation of esophageal mucosa, esophageal strictures, cough, asthma, laryngitis. ○ Barrett’s esophagitis - Transient lower esophageal sphincter relaxation is thought to be a major cause of GERD. This relaxation is mediated via vagal pathways and can be triggered by gastric distention HIATAL HERNIA Patho: Defect in the diaphragm that allows a portion of the stomach to pass through the diaphragmatic opening in the thorax. ○ Two Types: Sliding hernia: 3-10x more common incidence in women. Both a portion of the stomach and the gastroesophageal junction is above the diaphragmatic opening. Paraesophageal hernia: A greater part of the curvature of the stomach rolls through the diaphragmatic defect. Clinical Manifestations: Predisposition to GERD: heartburn, chest pain, dysphagia Can be incidentally found on x-ray. Cameron ulcers may develop on the mucosal surface of the stomach. Cameron ulcers are a mechanical phenomenon, related to extrinsic compression of the diaphragm on the stomach in patients with large hiatal hernias. If part of the stomach gets stuck above the diaphragm, could become incarcerated – life-threatening. BARRETT’S ESOPHAGUS Patho: a complication of chronic GERD that is characterized by intestinal metaplasia within the esophageal squamous mucosa and is associated with an increased risk of cancer  3 Risk Factors ○ Family hx ○ More common in white men ○ Typically presents age 40-60 ○ Chronic heartburn and acid reflux ○ Smoking =present or recent hx ○ Obesity ○ Increased risk of esophageal adenocarcinoma Clinical Manifestations ○ Heartburn, indigestion, regurgitation ○ Hoarseness ○ Chronic cough ○ Throat irritation - Diagnosis of Barrett esophagus requires endoscopic evidence of metaplastic columnar mucosa above the gastroesophageal junction. Microscopically, intestinal-type metaplasia is seen as replacement of the squamous esophageal epithelium with goblet cells. Goblet cells are diagnostic of Barrett esophagus and have distinct mucous vacuoles that stain pale blue and impart the shape of a wine goblet to the remaining cytoplasm. ESOPHAGEAL VARICES Patho: Complication of portal hypertension caused by cirrhosis of the liver. ○ Normal blood flow to the liver is obstructed. ○ Blood flows into the smaller blood vessels that are not designed to carry large amounts of blood. ○ The vessels may leak or rupture causing life-threatening bleeding. Risk Factors: ○ ETOH or cirrhosis of any cause. Chronic hepatitis B infection. Clinical Manifestations: ○ Vomiting of blood ○ Dark tarry stools Esophageal varices are caused by portal hypertension, which is due to impaired blood flow through the portal venous system and liver. Increased portal venous pressure results in the development of collateral channels at sites where the portal and caval systems communicate. These collateral veins allow some drainage to occur, but also result in congestion and dilation of subepithelial and submucosal venous plexuses within the distal esophagus and proximal stomach. These dilated vessels, termed varices, are common in patients with cirrhosis, most frequently due to alcoholic liver disease. ESOPHAGEAL CANCER Either Adenocarcinoma or squamous cell carcinoma Squamous cell carcinoma most common accounting for 1% to 2% of all cancers Men more than women (3x) Risk factors ○ Genetic, a diet high in nitrosamine content, chronic severe reflux (Barrett’s esophagus), environmental, smoking, alcohol, hx of Helicobacter pylori Prognosis ○ Poor; very high degree of metastasis GASTRITIS Patho: ○ Inflammation of the stomach lining Acute ○ Precipitated by ingestion of irritating substances Example: alcohol and aspirin, NSAIDs, viral, bacteria, autoimmune Chronic ○ Most often caused by H. pylori infection Risk Factors: ○ Chronic gastritis is almost always attributed to H-Pylori Clinical manifestations: ○ May be asymptomatic; anorexia, n/v, postprandial discomfort, hematemesis Complications: ○ Peptic ulcer disease, Atrophic gastritis, Gastric adenocarcinoma, Mucosa-associated lymphoid tissue lymphoma, Decreased acid and intrinsic factor PEPTIC ULCER DISEASE Patho: Disorders of the upper GI tract caused by the action of acid and pepsin - Peptic ulcer disease (PUD) refers to chronic mucosal ulceration affecting the duodenum or stomach and is almost always associated with H. pylori infection, NSAIDs, or cigarette smoking. The most common form of PUD occurs within the gastric antrum or duodenum as a result of chronic H. pylori–induced antral gastritis, which is associated with increased gastric acid secretion and decreased duodenal bicarbonate secretion.  4 GASTRIC DUODENAL Due to the breakdown of the protective mucous layer that Inappropriate excess secretion of acid normally prevents diffusion of acids into gastric epithelia due to Increased basal activity of vagus nerve chronic irritations Stimulates pyloric antrum cells to release gastrin to act Aspirin, NSAIDs, and bile acids on gastric parietal cells to release HCl Alcohol consumption may impair the alkalinity of the gastric Results in a high level of HCl mucosa Hyperplasia of the parietal cells in the stomach leads to an increased hydrochloric acid release Risk Factors: H-Pylori Infection, (No relation between diet and PUD), NSAIDs, stress (glucocorticoids), smoking, genetics, COPD, illicit drug use, Alcoholic cirrhosis ○ Viral infections (CMV, Herpes simplex virus) Clinical Manifestations: ○ Epigastric burning pain that is usually relieved by the intake of food (especially dairy products) or antacids ○ Pain of gastric ulcers typically occurs on an empty stomach but may present soon after a meal ○ Pain of duodenal ulcer classically occurs 2 to 3 hours after a meal and is relieved by further food ingestion Life-threatening complications, such as GI bleeding, may occur with no warning INTESTINAL OBSTRUCTION Patho: Partial or complete blockage of the small or large bowel ○ Mechanical: Adhesions, hernia, tumors, impacted feces, volvulus, intussusception ○ Functional: Conditions that inhibit peristalsis Ogilvie syndrome: characterized by recurrent bouts of ileus (rare) Contributing factors Previous abdominal surgery with adhesions Congenital abnormalities of the bowel Metastatic carcinoma, particularly cancer of the intestinal tract or female reproductive organs Fluid, gas, water, and electrolytes accumulate in the bowel Clinical manifestations: Depend on site and duration Mechanical obstructions: increased bowel sounds initially, accompanied by abdominal pain, nausea, and vomiting Functional obstructions: absence of bowel sounds Upper jejunal area: vomiting, dehydration, and electrolyte depletion Distal portion of the small bowel or ileum: constipation may be an early manifestation ○ If left uncorrected may cause perforation or ischemia (strangulation) and necrosis leading to bowel gangrene, sepsis, peritonitis, and shock VOLVULUS Patho: ○ Sudden, tight, twisting of the bowel impedes blood flow to the bowel ○ Impeded blood flow leads to gangrene, necrosis, and perforation ○ Life-threatening condition ○ Common sites are the cecum and sigmoid Risk Factors: ○ Results from an anomaly of rotation, ingested foreign body, or adhesion; cannot always be determined INTUSSUSCEPTION Patho: Telescoping/invagination of a portion of bowel into adjacent (usually distal) bowel causing intestinal obstruction Most often in infants; males more than females Gangrene, shock, and perforation if surgical treatment delayed ISCHEMIC BOWEL DISEASE GI tract is supplied by the celiac, superior mesenteric, and inferior mesenteric arteries PATHO: ○ Inadequate blood flow of oxygenated blood to the intestine ○ May be mild or severe RISK FACTORS ○ Atherosclerosis  5 ○ Hypotension ○ Thrombus ○ Bowel obstruction ○ Vasculitis ○ Cocaine or Meth CLINICAL MANIFESTATIONS ○ Pain on the left side of the belly ○ Tenderness or cramping in belling (sudden or gradual) ○ Bright red or maroon blood in the stool (may pass blood only and no stool) ○ Diarrhea ○ Nausea ○ Sudden urge to defecate - Intestinal responses to ischemia occur in two phases. The initial hypoxic injury occurs at the onset of vascular compromise, but the greatest damage occurs during the second phase, reperfusion injury, which is initiated by restoration of the blood supply. While the underlying mechanisms of reperfusion injury are incompletely understood, they include leakage of gut lumen bacterial products (e.g., lipopolysaccharide) into the systemic circulation, free radical production, neutrophil infiltration, and release of additional inflammatory mediators MALABSORPTION Characterized by defective absorption of fats, fat- and water-soluble vitamins, proteins, carbohydrates, electrolytes and minerals, and water Malabsorption results from a disturbance in at least one of the four phases of nutrient absorption: ○ Intraluminal digestion, in which proteins, carbohydrates, and fats are broken down into forms suitable for absorption ○ Terminal digestion, involving hydrolysis of carbohydrates and peptides by disaccharidases and peptidases in the brush border of the small intestinal mucosa ○ Transepithelial transport, in which nutrients, fluid, and electrolytes are transported across and processed within the small intestinal epithelium ○ Lymphatic transport of absorbed lipids DIARRHEA Defined as an increase in stool mass, frequency, or fluidity, typically greater than 200 g per day ○ Typically does not require additional testing if no fever, chills, or blood present Diarrhea can be classified into four major categories ○ Secretory diarrhea is characterized by isotonic stool and persists during fasting. ○ Osmotic diarrhea, such as occurs with lactase deficiency, is due to the excessive osmotic force exerted by unabsorbed luminal solutes. The diarrhea fluid is more than 50 mOsm more concentrated than plasma, and diarrhea abates with fasting. ○ Malabsorptive diarrhea follows the generalized failure of nutrient absorption, is associated with steatorrhea, and is relieved by fasting. ○ Exudative diarrhea due to inflammatory disease is characterized by purulent, often bloody stools that continue during fasting CELIAC DISEASE (CELIAC SPRUE) - Celiac disease, also known as celiac sprue or gluten-sensitive enteropathy, is an immune-mediated disorder triggered by the ingestion of gluten-containing foods such as wheat, rye, or barley in genetically predisposed individuals. PATHO RISK FACTORS CLINICAL MANIFESTATIONS Familial intolerance of gluten-containing Family member with celiac Diarrhea/Constipation foods Type 1 DM Fatigue Immune reaction in the small intestine Down syndrome or Turner Weight loss Leads to inflammation and atrophy of the syndrome Bloating and gas intestinal villi Addison's Disease Abdominal pain Impaired nutrient absorption Autoimmune thyroid disease Nausea and vomiting Reduced surface area Anemia Decreased brush border enzymes Loss of bone density Increase for intestinal malignancy Dermatitis Mouth ulcers INFECTIOUS ENTEROCOLITIS - Infectious Enterocolitis - can present with a broad range of symptoms including diarrhea, abdominal pain, urgency, perianal discomfort, incontinence, and hemorrhage PSEUDOMEMBRANOUS COLITIS CAMPYLOBACTER SALMONELLA ENTEROCOLITIS  6 PATHO Acute inflammation and Most common bacterial Classified within the necrosis of large intestine enteric pathogen in Enterobacteriaceae family of Caused by Clostridioides high-income countries gram-negative bacilli difficile (formerly Clostridium and is an important cause Non-typhoid Salmonella such difficile) of traveler's diarrhea and as S. enteritidis Mediated by bacterial toxins food poisoning RISK Antibiotics Associated with ingestion Most common in young children FACTORS Disruption of the normal colonic of improperly cooked and older adults microbiota by antibiotics allows chicken, but outbreaks Transmitted via contaminated C. difficile overgrowth. can also be caused by food, particularly raw or unpasteurized milk or undercooked meat, poultry, contaminated water eggs, and milk CLINICAL Diarrhea (often bloody), Self-limited disease Loose stools to cholera-like MANIFESTATI abdominal pain, fever, characterized by 7 to 10 profuse diarrhea to dysentery ONS leukocytosis, sepsis, colonic days of diarrhea Fever often resolves within 2 perforation (rare) Fever days Abdominal pain Diarrhea can persist for a week Organisms can be shed in the stool for several weeks after resolution IRRITABLE BOWEL SYNDROME Patho: ○ Alternating diarrhea and constipation accompanied by abdominal cramping pain with no identifiable pathologic process in the GI tract Also called spastic colitis and irritable colon syndrome Etiology: unclear but slow wave activity of bowel is increased ○ May be due to psychologic stressors, diet, perturbation of the gut microbiome, increased enteric sensory responses to GI stimuli, and abnormal GI motility Clinical manifestations ○ Diarrhea or constipation or an alternating pattern of both, abdominal cramping pain, mucus in stool, nausea It should be recognized that IBS is a syndrome and that multiple illnesses may be represented under this global descriptor. IBS is currently divided into diarrhea-predominant, constipation-predominant, and mixed subtypes, as defined by successive revisions of the Rome criteria. INFLAMMATORY BOWEL DISEASE Chronic condition resulting from complex interactions between intestinal microbiota and host immunity in genetically predisposed individuals that leads to inappropriate mucosal immune activation 2 disorders comprise IBD: ulcerative colitis and Crohn’s disease The distinction between ulcerative colitis and Crohn disease is primarily based on the distribution of affected sites (Fig. 17.33) and the morphologic expression of disease (Table 17.8) at those sites. Ulcerative colitis involves only the colon and rectum and is generally limited to the mucosa and submucosa. In contrast, Crohn disease, which has also been referred to as regional enteritis (because of frequent ileal involvement) may involve any area of the GI tract and is typically transmural. CROHN’S DISEASE Patho: ○ Affects the proximal portion of the colon or terminal ileum ○ Chronic inflammation of all layers of the intestinal wall resulting from blockage and inflammation of lymphatic vessels ○ Suggestive findings are ulcerations, strictures, fibrosis, and fistulas Clinical manifestations ○ Intermittent bouts of fever, diarrhea, if bloody, not as severe as ulcerative colitis; constant, chronic RLQ pain, may have RLQ mass, tenderness ○ Iron deficiency anemia ○ Fibrosing strictures The presence of multiple, separate, sharply delineated areas of disease, resulting in skip lesions, is characteristic, and when present, differentiates Crohn disease from ulcerative colitis. ULCERATIVE COLITIS Patho: ○ Chronic inflammatory disease of the mucosa of the rectum and colon  7 ○ Begins as inflammation at the base of crypts of Lieberkühn; damage results ○ Abscess formation in crypts; abscesses begin to coalesce, and large ulcerations develop in the epithelium Large ulcers form in the mucosal layer of the colon and rectum RISK FACTORS: ○ Associated with increased cancer risk after 7 to 10 years of disease ○ Have exacerbations and remissions CLINICAL MANIFESTATIONS ○ Are bloody diarrhea and lower ○ Abdominal pain Ulcerative colitis should follow high fiber, low-residue diet IE: vegetables (juice/cooked/canned), ground beef, veal, pork, lamb, white rice, pasta DIVERTICULAR DISEASE Patho: ○ Presence of diverticula (herniations) in the colon: diverticulosis ○ Results from low intake of dietary fiber ○ Inflamed herinations in the sigmoid colon Clinical manifestations ○ Diverticulosis—asymptomatic ○ Diverticulitis (inflamed diverticuli)—fever, acute lower abdominal pain, leukocytosis POLYPS Most common in the colon and rectum but may occur in the esophagus, stomach, or small intestine Polyps begin as small elevations of the mucosa = referred to as sessile, (grow directly from the stem without a stalk) As sessile polyps enlarge, the proliferation of cells adjacent to the mass and the effects of traction on the luminal protrusion may combine to create a stalk. Polyps with stalks are termed pedunculated. Intestinal polyps can be classified as nonneoplastic or neoplastic Most common neoplastic polyp is the adenoma, which has the potential to progress to cancer. Nonneoplastic polyps can be classified as inflammatory, hamartomatous, or hyperplastic INFLAMMATORY POLYPS Form as part of the solitary rectal ulcer syndrome and is an example of a purely inflammatory lesion PATHO: ○ Impaired relaxation of the anorectal sphincter that creates a sharp angle at the anterior rectal shelf and leads to recurrent abrasion and ulceration of the overlying rectal mucosa CLINICAL MANIFESTATIONS: ○ Clinical triad of rectal bleeding, mucus discharge, and an inflammatory lesion of the anterior rectal wall. NEOPLASTIC POLYPS Most common neoplastic polyps are colonic adenomas, which are precursors to the majority of colorectal adenocarcinomas ○ Surveillance is recommended beginning at age 45 to 50 Adenomas are epithelial neoplasms that range from small, often pedunculated, polyps to large sessile lesions Most colorectal adenomas are benign lesions, A small proportion harbor invasive cancer at the time of detection Size is the most important characteristic that correlates with the risk of malignancy COLON CANCER Second only to lung cancer as a cause of cancer deaths Risk factors ○ Increases after age 40 ○ High-fat, low-fiber diet ○ Polyps ○ Chronic irritation or inflammation ○ Hereditary Clinical manifestations ○ Right side: black, tarry stools ○ Left side: intermittent abdominal cramping and fullness; “ribbon” or pencil-shaped stools; blood or mucus in stool  8 ○ Rectum: change in bowel habits; urgent need to defecate on awakening; alternating constipation and diarrhea; sensation of rectal fullness; a dull ache in rectum/sacral region Most common neoplastic colon polyp is adenoma. HEMORRHOIDS Develop secondary to persistently elevated venous pressure within the hemorrhoidal plexus Most frequent predisposing influences are straining at defecation, constipation, and venous stasis of pregnancy Hemorrhoids may also develop secondary to portal hypertension. ○ Hemorrhoids (anal varices) are similar in portal hypertension is similar to esophageal varices ○ Anal varices are both more common and much less serious. ○ Anal and perianal varices connect portal and caval venous systems, thereby relieving venous hypertension. Hemorrhoids often present with pain and rectal bleeding ○ Bright red blood seen on toilet tissue. ○ Except for pregnant women, hemorrhoids are rarely encountered in persons younger than age 30. APPENDICITIS Patho: ○ initiated by progressive increases in intraluminal pressure that compromise venous outflow ○ Inflammation of the vermiform appendix ○ Overt luminal obstruction, usually caused by a small stone-like mass of stool, or fecalith, or, less commonly, a gallstone, tumor, or mass of worms Clinical manifestations ○ Periumbilical pain, RLQ pain (“McBurney’s point”) (classic, but may be anywhere), nausea, vomiting, fever, diarrhea, RLQ tenderness, rebound tenderness, systemic signs of inflammation. A classic physical finding is the McBurney sign, deep tenderness located two-thirds of the distance from the umbilicus to the right anterior superior iliac spine (McBurney point). FEATURES OF LIVER DISEASE Vulnerable to a wide variety of metabolic, toxic, microbial, circulatory, and neoplastic insults. Hepatic damage secondary to other diseases, such as heart failure, disseminated cancer, and extrahepatic infections. Deranged liver function may become life-threatening Cirrhosis is associated with continuous inflammation of the bile ducts Except for acute liver failure, Liver disease is an insidious process in which clinical detection and symptoms of hepatic decompensation may occur weeks, months, or many years after the onset of the injury. May be imperceptible to the patient and detectable only by abnormal laboratory tests  9 GENERAL MANIFESTATIONS OF LIVER DISEASE Attributable to hepatocellular failure and portal hypertension Hepatocellular failure Inadequate protein metabolism ○ Decreased production of clotting factors (excessive bleeding) ○ Hypoalbuminemia: generalized edema related to low serum oncotic pressure Impaired processing of endogenous steroid hormone: estrogen ○ Men: gynecomastia, impotence, testicular atrophy, female hair distribution ○ Women: irregular menses, palmar erythema, spider telangiectasia Impaired clearance of exogenous drugs and toxins ○ Conversion of ammonia to urea Clinical manifestations: ○ Jaundice, Muscle wasting, Ascites, ○ Impaired absorption of fat-soluble vitamins: A, D, E, and K ○ Altered lipoprotein processing, Dyslipidemias: hypertriglyceridemia ○ Abnormal storage and release of glucose in the form of glycogen: Hyperglycemia, Hypoglycemia ○ Osteomalacia ○ Edema in advanced disease due to decreased plasma colloid oncotic pressure. PORTAL HYPERTENSION Intrahepatic vascular resistance increases pressure in portal circulation. ○ Increased resistance to portal blood flow may develop in a variety of circumstances, which can be divided into prehepatic, intrahepatic, and posthepatic. The major prehepatic conditions are obstructive thrombosis, narrowing of the portal vein before it ramifies within the liver, or massive splenomegaly with increased splenic vein blood flow. The main posthepatic causes are severe right-sided heart failure, constrictive pericarditis, and hepatic vein outflow obstruction. The dominant intrahepatic cause is cirrhosis, accounting for most cases of portal hypertension. Far less frequent intrahepatic causes are schistosomiasis, massive fatty change, diffuse fibrosing granulomatous disease such as sarcoidosis, and diseases affecting the portal microcirculation such as nodular regenerative hyperplasia. Congested venous drainage of the GI tract Etiology ○ Alcoholic or post-hepatic cirrhosis ○ Infection from liver flukes ○ Vasoactive hormones ○ Increased splanchnic blood flow ○ Increased vascular resistance in the liver Clinical manifestations ○ Anorexia ○ Varices (esophageal, gastric, hemorrhoidal) can rupture; causing uncontrolled bleeding ○ Ascites ○ Splenomegaly The four major consequences of portal hypertension are (1) hepatic encephalopathy (described under liver failure), (2) ascites, (3) the formation of portosystemic venous shunts, and (4) congestive splenomegaly. Portal hypertension and hypoalbuminemia contribute to development of ascites HEPATIC ENCEPHALOPATHY Pathogenesis ○ Complex neuropsychiatric syndrome from too much ammonia ○ Associated with hepatic failure or severe chronic liver disease Exact cause is unknown ○ Precipitated by conditions that increase protein metabolism (GI hemorrhage and increased protein consumption), and by conditions that further impair hepatocyte function Clinical manifestations ○ Dementia ○ Psychotic symptoms ○ Spastic myelopathy ○ Cerebellar/extrapyramidal signs ○ Asterixis “liver flap” (classic sign) ○ Spastic jerking of hands held in forced extension ○ Ammonia level correlates positively with the level of encephalopathy ○ Mild confusion and lethargy to stupor and coma (Grade 1 to 4)  10 LIVER FAILURE Liver failure may follow acute injury or chronic injury but may also occur as an acute insult superimposed on an otherwise well-compensated chronic liver disease. The mnemonic for causes of acute liver failure is as follows: ○ A: Acetaminophen, hepatitis A, autoimmune hepatitis ○ B: Hepatitis B ○ C: Hepatitis C, cryptogenic ○ D: Drugs/toxins, hepatitis D ○ E: Hepatitis E, esoteric causes (e.g., Wilson disease, Budd-Chiari syndrome, lymphoma, carcinoma) ○ F: Fatty change of the microvesicular type (e.g., fatty liver of pregnancy, valproate, tetracycline, Reye syndrome) Serious and sometimes fatal sequelae of liver failure include coagulopathy, encephalopathy, portal hypertension, bleeding esophageal varices, hepatorenal syndrome, and portopulmonary hypertension. VIRAL HEPATITIS Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E Serum aminotransferase is usually 10x the normal limit in viral hepatitis The term “viral hepatitis” is most commonly used in the context of liver involvement by hepatotropic viruses, which include hepatitis A, B, C, D, and E. Nonhepatotropic viruses such as Epstein-Barr virus, cytomegalovirus, herpes simplex virus, adenovirus, and yellow fever virus can also cause hepatitis, often in association with systemic infection. HEPATITIS A (HAV) RNA virus spread by the fecal-oral route Also called enteric hepatitis 2 to 7-week incubation period Prodromal period ○ Jaundice, RUQ pain. malaise, anorexia, nausea, low-grade fever, children may not experience jaundice Followed by jaundice lasting approx 2 weeks Self-limited course Serologic testing ○ Anti-HAV IgG (previous infection) ○ IgM (acute infection) IgM antibody against HAV appears with the onset of symptoms and persists for 3 to 6 months. IgG anti-HAV appear during recovery from the acute infection and persists for years, conferring lifelong immunity against reinfection. Hepatitis A virus (HAV) infection is a self-limited disease and does not lead to chronic hepatitis or a carrier state HEPATITIS B (HBV) Partially double-stranded DNA virus Spread by parenteral contact with infected blood or blood products ○ Includes contaminated needles and sexual contact Risk factors ○ Perinatal, health care settings (3%); transfusions and dialysis (1%); acupuncture, tattooing, extended overseas travel, residence in an institution Incubation period of 2 to 6 months Prodromal period ○ Asymptomatic or rashes, arthralgia, arthritis, angioedema, serum sickness, glomerulonephritis, jaundice (lasting 2 weeks on average) High –risk for development of hepatocellular carcinoma Serologic testing Surface antigen (HBsAg): early/active and chronic infection  11 Surface antibody (HbsAb): resolution and immunity Core antigen (HBcAg): appears first in active infection Core antibody (HBcAb): seroconversion Hepatitis B e antigen (HBeAg): viral replication and infectivity The major clinical presentations include: (1) acute hepatitis followed by recovery and clearance of the virus, (2) acute hepatic failure with massive liver necrosis, (3) chronic hepatitis with or without progression to cirrhosis, and (4) an asymptomatic, “healthy” carrier state. Vaccination is highly effective, as it induces a protective anti-HBs antibody response in 95% of infants, children, and adolescents. Although vaccine-induced escape mutants that replicate in the presence of vaccine-induced immunity have been described, these do not appear to be increasing in prevalence. In those with chronic HBV, treatment with interferon and antiviral agents such as reverse transcriptase inhibitors (entecavir, tenofovir) can slow disease progression, reduce liver damage, and lower the risk of cirrhosis and hepatocellular carcinoma, but complete cure is difficult. The course of the infection is followed by measuring viral antigens and serologic responses in the blood: HBsAg appears before the onset of symptoms and peaks in acute, symptomatic disease. In those who clear the infection, it often declines to undetectable levels in 12 weeks, but can be present for as long as 24 weeks. By contrast, HBsAg persists in cases that progress to chronicity. Anti-HBs antibody begins to rise following the resolution of acute disease, generally after the disappearance of HBsAg. In some cases, the appearance of anti-HBs antibody is delayed until weeks to months after disappearance of HBsAg; in such instances, the serologic diagnosis can be made by detection of IgM anti-HBc antibody. Anti-HBs antibodies tend to persist for life, conferring protection; this is the basis for current vaccination strategies using noninfectious HBsAg. By contrast, anti-HBs antibodies are not produced in cases that progress to chronic liver disease, which is also associated with variable persistent elevations of serum transaminases in most (but not all) cases. HBeAg, HBV DNA, and HBV DNA polymerase are detectable in the serum soon after HBsAg and signify active viral replication. Persistence of HBeAg is an important indicator of continued virus replication, infectivity, and probable progression to chronic hepatitis. One caveat is that mutated strains of HBV can emerge that do not produce HBeAg, but are replication competent and express HBcAg. In such patients, the HBeAg may be low or undetectable despite the presence of serum HBV DNA. Anti-HBe antibody signifies that acute infection has peaked and is on the wane, whereas in cases that progress to chronic infection, anti-HBe antibody is not produced or appears only late in the disease course. HEPATITIS C (HCV) Single-stranded RNA virus (Flavivirus) Spread through IV drug use or blood transfusions prior to 1990 Have 6 types ○ Type 1: most common in the United States but has a lower response rate to treatment ○ Types 2 and 3: common in N. America ○ Types 4 to 6: common overseas Acute HCV infection ○ Usually asymptomatic ○ Course is erratic with wide fluctuations on liver enzymes Chronic HCV infection ○ Usually asymptomatic until advanced liver disease intervenes ○ Most common cause of end-stage liver disease with cirrhosis HEPATITIS D - DELTA Defective RNA virus that requires the helper function of HBV to replicate Infection appears to accelerate and worsen HBV infection symptoms Prevention of HBV infection also prevents HDV infection Transmitted parenterally and intimate contact Diagnosis ○ Anti-HDV IgM and IgG enzyme linked immunosorbentassay (ELISA) Hepatitis D virus (HDV) or “the delta agent,” is a unique RNA virus that is dependent for its life cycle on HBV. HEPATITIS E (HEV) RNA virus spread via fecal-oral route ○ Contaminated H2O ○ Parenteral transmission Most common in developing countries or recent travel to these areas Relatively high mortality rate in pregnant women Incubation period is 2 to 9 weeks Prodromal and icteric illness  12 ○ Usually lasts only 2 weeks ○ Similar to HAV infection CHRONIC HEPATITIS Group of diseases characterized by inflammation of the liver that lasts 6 months or longer ○ Causes Autoimmune disease Viral hepatitis (B and C) Toxins Metabolic diseases The defining histologic feature of chronic viral hepatitis is portal lymphocytic, or lymphoplasmacytic, inflammation with fibrosis. The inflammatory cells often cross the limiting plate and lead to injury of periportal hepatocytes. This may be accompanied by a variable degree of lobular inflammation. Fibrosis develops with increasing liver damage manifesting initially as portal and periportal fibrosis. Fibrous septa develop and lead to portal bridging fibrosis, and eventually cirrhosis. CHRONIC PERSISTENT HEPATITIS CHRONIC ACTIVE HEPATITIS Pathogenesis Progressive, destructive inflammatory disease of the liver lasting >6 ○ Chronic low-grade liver inflammation of any months cause (also called “triaditis” or “transaminitis”) ○ Extends beyond the portal triad to hepatic lobule ○ Inflammation confined to portal triads without (piecemeal necrosis) destruction of normal liver structures May progress to cirrhosis, end-stage liver disease, liver fibrosis Clinical manifestations ○ Asymptomatic or mild, nonspecific symptoms Clinical manifestations Fatigue, malaise, nausea, anorexia, ascites, hepatomegaly, abdominal pain, and jaundice Diagnosis Laboratory: Abnormal liver enzymes & serologic studies Liver biopsy: Confirms diagnosis ○ Grading and staging - This is defined as symptomatic, biochemical, or serologic evidence of continuing or relapsing hepatic disease for more than 6 months. In some patients, persistent elevation of serum transaminases may be the only clinical evidence of chronicity. Prolongation of the prothrombin time, hyperglobulinemia, hyperbilirubinemia, and mild elevations in alkaline phosphatase level can occur. In symptomatic individuals, the most common finding is fatigue; less common symptoms are malaise, loss of appetite, and occasional bouts of mild jaundice. Immune complex disease can develop due to circulating antibody-antigen complexes in chronic HBV and HCV infection, and can manifest as vasculitis, glomerulonephritis, and cryoglobulinemia. AUTOIMMUNE HEPATITIS Chronic, progressive hepatitis associated with genetic predisposition, autoantibodies, and therapeutic response to immunosuppression Female predominance PATHO: ○ Strong association with specific HLA alleles in Caucasians (DR3), Japanese (DR4), and in South Americans (DRB1). ○ Proposed triggers for the immune reaction include viral infections, drugs/toxins, and vaccination, but the antigens that are the target of autoimmunity are unknown Diagnosis ○ Several autoantibodies ○ Positive ANA (high level) ○ High levels of anti-smooth muscle antibodies - The diagnosis of autoimmune hepatitis is based on a combination of four features: autoantibodies, elevated serum IgG, pathologic findings, and exclusion of viral/drug etiologies. Typical histologic features of autoimmune hepatitis include a high degree of necroinflammatory activity and numerous plasma cells. EFFECTS OF ALCOHOL (pg. 417 - 419) Ethanol is absorbed unaltered in the stomach and small intestine and then distributes throughout the body in direct proportion to the blood level. ○ Less than 10% is excreted unchanged in the urine, sweat, and breath Drowsiness occurs at 200 mg/dL, stupor at 300 mg/dL, and coma, with possible respiratory arrest, at higher levels  13 Acute alcoholism exerts its effects mainly on the CNS, but it may induce hepatic and gastric changes that are reversible if alcohol consumption is discontinued CNS ○ Alcohol is a depressant affecting subcortical structures that modulate cerebral cortical activity. ○ At higher blood levels, cortical neurons and lower medullary centers are depressed, including those regulating respiration. ○ Respiratory arrest may follow - Most of the alcohol in the blood is metabolized to acetaldehyde in the liver by three enzyme systems: alcohol dehydrogenase, cytochrome P-450 isoenzymes, and catalase Chronic alcoholism affects not only the liver and stomach but virtually all other organs and tissues as well. ○ Significant morbidity and a shortened lifespan, related principally to damage to the liver, gastrointestinal tract, CNS, cardiovascular system, and pancreas ○ The main effects are fatty liver, alcoholic hepatitis, and cirrhosis, which leads to portal hypertension and increases the risk for the development of hepatocellular carcinoma ○ Can cause bleeding from gastritis and gastric ulcers, peripheral neuropathy associated with thiamine deficiency, alcoholic cardiomyopathy, and acute and chronic pancreatitis ○ Major risk factor for cancers of the oral cavity, larynx, and esophagus. The risk is greatly increased by concurrent smoking or the use of smokeless tobacco Moderate intake of alcohol, multiple fat droplets accumulate in the cytoplasm of hepatocytes (fatty change or hepatic steatosis) Gastric changes are acute gastritis and ulceration ALCOHOLIC LIVER DISEASE Major cause of liver disease in most Western countries There are three distinctive forms of alcohol-induced liver injury: ○ (1) steatosis, or fatty change ○ (2) alchoholic steato-hepatitis ○ (3) fibrosis, which leads to cirrhosis Diagnosis ○ AST (SGOT) markedly > ALT (SGPT) Pathogenesis Active inflammation of the centrilobular region of the liver Liver cells show pathologic changes of hepatocyte necrosis with neutrophilic infiltration and intracellular inclusions (Mallory bodies) Causes: Alcoholics binge in larger quantities than usual Mortality rate 33% Clinical manifestations Illness ranges from mild to severe (severe: hepatomegaly, fever, acute liver failure, encephalopathy) May be complicated by acute alcohol withdrawal and delirium tremens - Excessive alcohol intake causes steatosis, dysfunction of mitochondria, microtubules and cellular membranes, and oxidative stress, and the resulting injury leads to varying degrees of inflammation and hepatocyte death - There are three distinctive, albeit overlapping, forms of alcohol-induced liver injury: (1) steatosis, or fatty change, (2) alcoholic steato-hepatitis, and (3) fibrosis, which leads to cirrhosis. - FIGURE 18.17 Alcoholic liver disease. The interrelationships among hepatic steatosis, alcoholic hepatitis, and alcoholic cirrhosis are shown, along with depictions of key morphologic features. It should be noted that some patients present initially with cirrhosis without any of the other forms of alcoholic liver disease. NONALCOHOLIC FATTY LIVER DISEASE (NALFD) Presence of hepatic steatosis (fatty liver) in individuals who do not consume alcohol or do so in small quantities and who do not have another cause of secondary hepatic fat accumulation Associated with obesity, diabetes mellitus type 2, and hyperlipidemia, all components of the metabolic syndrome  14 Set to become the most common cause of chronic liver disease in the United States and is projected to exceed 30% prevalence in the adult population by 2030 The term nonalcoholic steatohepatitis (or NASH) is reserved for NAFLD patients who demonstrate steatohepatitic injury with histologic features similar to those seen with alcoholic hepatitis. PATHO: precise mechanisms underlying NAFLD are unknown. RISKS: ○ Strong association with insulin resistance ○ Established an association between increased gut-derived endotoxin production and liver inflammation and injury. ○ High-fructose diets have also been associated with an increased risk of NAFLD-related fibrosis, and dietary fat, particularly trans-fat, may have a role in producing liver injury. ○ Obstructive sleep apnea, usually occurring in the setting of obesity, has been associated with disease progression, possibly related to intermittent hypoxia CLINICAL MANIFESTATIONS: ○ Individuals with only steatosis are generally asymptomatic. ○ Clinical presentation is often related to other signs and symptoms of the metabolic syndrome, in particular, insulin resistance or diabetes mellitus ○ Imaging studies may reveal fat accumulation in the liver. ○ Liver biopsy is required for a diagnosis of NASH and aids in the assessment of fibrosis. ○ Serum AST and ALT are elevated in most patients with NASH. ○ Despite the enzyme elevations, patients may be asymptomatic. ○ Fatigue or complain of right-sided abdominal discomfort caused by hepatomegaly - Nonalcoholic steatohepatitis (or its common acronym NASH) is reserved for NAFLD patients who demonstrate steatohepatitic injury with histologic features similar to those seen with alcoholic hepatitis. - - - NASH shares many morphologic features with alcoholic hepatitis; steatosis (≥5% of hepatocytes), lobular inflammation, and ballooned hepatocytes are required for its diagnosis. HEMOCHROMATOSIS (HEREDITARY HEMOCHROMATOSIS) Caused by excessive iron absorption, most of which is deposited in the liver and pancreas, followed by the heart, joints, and endocrine organs Inherited disorder- hereditary hemochromatosis Parenteral administration of iron, or other causes (secondary hemochromatosis) PATHO: ○ There is no regulated iron excretion from the body, the total body content of iron is tightly regulated by intestinal absorption. ○ In hereditary hemochromatosis, regulation of intestinal absorption of dietary iron is abnormal, leading to net iron accumulation of 0.5 to 1 g/year ○ Disease typically manifests after 20 g of stored iron has accumulated. ○ Main regulator of iron absorption is the protein hepcidin, encoded by the HAMP gene and produced and secreted by the liver - When hemochromatosis results from an inherited disorder, it is referred to as hereditary hemochromatosis. When accumulation occurs as a consequence of parenteral administration of iron, usually in the form of transfusions, or other causes, it is called secondary hemochromatosis. - Iron accumulation in hereditary forms is lifelong, but the injury caused by excessive iron is slow and progressive; hence symptoms usually first appear in the fourth to fifth decades of life in men and later in women since menstrual bleeding counterbalances the accumulation until menopause. - Because many women do not accumulate clinically relevant amounts of iron within their lifetime, hereditary hemochromatosis affects more males than females (ratio of 5 to 7 : 1). CLINICAL MANIFESTATIONS: Hepatomegaly Abdominal pain Abnormal skin pigmentation (particularly in sun-exposed areas) Deranged glucose homeostasis or diabetes mellitus (due to destruction of pancreatic islets) Cardiac dysfunction (arrhythmias, cardiomyopathy) Atypical arthritis More often a disease of males Rarely becomes evident before 40 years of age. The classic tetrad of cirrhosis with hepatomegaly, abnormal skin pigmentation, diabetes mellitus, and cardiac dysfunction may not develop until late in the course. Death may result from cirrhosis or cardiac disease. In some-presenting complaint is hypogonadism (e.g., amenorrhea in the female, impotence, and loss of libido in the male) 𝛼₁-ANTITRYPSIN DEFICIENCY Pathogenesis ○ Causes liver disease because of hepatocellular accumulation of the misfolded protein, an example of a “toxic gain-of-function” mutation Defective α1-antitrypsin protein accumulates in the liver; produces diagnostic granules  15 CLINICAL MANIFESTATIONS Findings and courses are quite variable. Neonatal presentations tend to be associated with severe disease and rapid progression to cirrhosis. In adulthood -chronic hepatitis, cirrhosis, or hepatocellular carcinoma Pancreatic insufficiency - α1-Antitrypsin deficiency is an autosomal recessive disorder of protein folding marked by very low levels of circulating α1-antitrypsin (α1AT). The major function of this protein is the inhibition of proteases, particularly neutrophil elastase, cathepsin G, and proteinase 3, which are normally released from neutrophils at sites of inflammation. α1AT deficiency leads to the development of pulmonary emphysema, because the activity of neutrophil elastases is not inhibited (Chapter 15). It also causes liver disease as a consequence of hepatocellular accumulation of the misfolded protein, an example of a “toxic gain-of-function” mutation. HEPATOCELLULAR CARCINOMA Liver is a common site for metastasis of primary cancers ○ Esophagus, stomach, colon, rectum, breast, and lung ○ Related to vascularity and lymphatic drainage Hepatocellular carcinoma most common form of primary hepatic malignancy Referred to as “hepatoma,” HCC Common in middle-aged; Men > women Increase in United States related to increased HBV and HCV prevalence Clinical manifestations Hepatomegaly Abdominal pain Nausea, weight loss Jaundice, ascites (advanced) Paraneoplastic syndromes Hypercalcemia, erythrocytosis, hypoglycemia, thyrotoxicosis, hypertrophic osteoarthropathy (finger clubbing) HYPERBILIRUBINEMIA (JAUNDICE) Characteristic sign of liver disease Green-yellow staining of tissues by bilirubin Results from impaired bilirubin metabolism Pathogenesis 1.Damaged RBCs release Hgb 2.Heme and globin separate 3.Heme releases iron and biliverdin 4.Biliverdin à (bilirubin reductase)à bilirubin 5.Bilirubin (unconjugated, lipid soluble) is released into plasma and transported to liver by albumin 6.In the liver, bilirubin is bound (conjugated) to glucuronic acid by uridine diphosphate glucuronosyltransferase (UDPGT) 7. Yields H2O-soluble bilirubin - excreted into bile ducts 8.Bilirubin as a component of bile is transported to the small intestine 9. Passes to the colon to be broken down to urobilinogen and passed in feces 10. Small fraction absorbed back into circulation to be excreted by kidneys 11. Jaundice results from dysfunction anymore along the pathway  16 BILIRUBIN METABOLISM JAUNDICE Prehepatic causes ○ Hemolysis, ineffective erythropoiesis, resorption of large hematomas Hepatic causes ○ Dysfunction of liver cells: increased levels of conjugated bilirubin; immature UDPGT: physiologic newborn jaundice, UDPGT mutations Underlying causes ○ Alcoholic liver disease, drug reaction, metastatic or primary malignancy LIVER DISEASES AND PEDIATRIC CONSIDERATIONS Physiologic jaundice of the newborn Harmless condition lasting no longer than 2 weeks after delivery Causes ○ Immature bilirubin conjugation and transport mechanisms ○ Increased gut absorption of bilirubin ○ Breast-fed > bottle-fed babies: B-glucuronidase in breast milk results in increased unconjugated bilirubin in the gut HEPATIC DISEASE ASSOCIATED WITH PREGNANCY Hepatic disease may be exacerbated by pregnancy. Viral hepatitis (HAV, HBV, HCV, or HBV + HDV) is the most common cause of jaundice in pregnancy small subgroup of pregnant women (0.1%) have more serious hepatic complications.  17 These disorders include preeclampsia and eclampsia, acute fatty liver of pregnancy, and intrahepatic cholestasis of pregnancy PREECLAMPSIA AND ECLAMPSIA Preeclampsia affects up to 10% of pregnancies and is characterized by maternal hypertension, proteinuria, peripheral edema, and coagulation abnormalities When hyperreflexia and convulsions occur, the condition is called eclampsia and may be life-threatening Subclinical hepatic disease may be the primary manifestation of preeclampsia, as part of a syndrome of hemolysis, elevated liver enzymes, and low platelets dubbed the HELLP syndrome CLINICAL FEATURES ○ Modest to severe elevation of serum aminotransferases ○ Mild elevation of serum bilirubin. ○ Hepatic dysfunction sufficient to cause coagulopathy signifies advanced and potentially lethal disease. LIVER DISEASES AND GERIATRIC CONSIDERATIONS Liver size and blood flow decrease with aging Careful monitoring of medications that affect hepatic blood flow and are processed by cytochromes Ischemic hepatitis Associated with cardiovascular disease and episodes of hypotension; more common in older patients Rapid elevation of serum transaminases and prolonged PT Recovery may be rapid but depends on the severity of the underlying disorder Autoimmune liver diseases Chronic active hepatitis may be the cause of “cryptogenic”cirrhosis in older women Primary sclerosing cholangitis Affects older persons with long-standing ulcerative colitis, even those with colectomies performed many years earlier GALLBLADDER Pathophysiology of Cholesterol Gallstone Formation Lecithin: helps keep cholesterol from precipitating into crystals in bile Crystals of cholesterol may initiate gallstone formation Relative concentrations of cholesterol, lecithin, and bile acids: determine the likelihood of cholesterol gallstone formation Risk Factors Prolonged fasting or rapid weight loss, Pregnancy, Oral contraceptives, Obesity, Age, Sex CHOLELITHIASIS (GALLSTONES) Pathophysiology of Cholesterol Gallstone Formation Majority of gallstones are cholesterol 3 phases ○ Supersaturation of bile with cholesterol causing precipitation of cholesterol ○ Nucleation of crystals ○ Hypomotility (stasis of bile) allowing stone growth Etiology ○ Native Americans > American Caucasians ○ Women > men (2:1) Adults ○ May be asymptomatic and not need treatment Children ○ Usually from an underlying condition and need gallbladder removed GALLBLADDER: CHRONIC CHOLELITHIASIS Biliary colic - RUQ pain Related to intermittent obstruction of the cystic duct Precipitated by a meal (infrequent schedule) Persistent epigastric or right upper abdominal pain, often radiates to the back Nausea, vomiting, sweating, flatus ○ Intermittent pain due to eating schedule Increases steadily for >15 minutes, lasts several hours, then slowly decreases Fatty food intolerance, belching, bloating, and epigastric burning  18 GALLBLADDER: CHOLECYSTITIS Inflammation of the gallbladder wall Causes fibrosis and thickening Related to the continued presence of gallstones 2 types: Acute and Chronic 1. ACUTE CHOLECYSTITIS ○ Acute inflammation of the gallbladder wall ○ Etiology Cholelithiasis present in 90% of patients Obstruction of cystic duct present in almost all patients: related to stasis of bile Bacterial infection may be present ○ If untreated, escalates; gangrene may occur Rupture Peritonitis Septic shock Localized abscess (empyema) Cholecystoenteric fistula (fistula between gallbladder and GI tract) Clinical manifestations ○ Severe, right upper abdominal pain radiates to back; abdominal tenderness; fever and chills, leukocytosis, mild elevations of bilirubin and serum transaminases Acalculous cholecystitis ○ Occurs in patients without preexisting gallstones ○ Males >50 years ○ Tends to occur in the setting of major surgery, critical illness, trauma, burn-related injury, or TPN ○ Rapid development of gangrene, perforation, emphysematous cholecystitis, and empyema 2. CHRONIC CHOLECYSTITIS Patho: ○ Chronic inflammation of gallbladder wall ○ Related to persistent low-grade irritation from gallstones; recurrent attacks of acute cholecystitis ○ Predisposing factors: diabetes, obesity Clinical manifestations ○ Asymptomatic; intermittent biliary colic or symptomatic acute attacks ○ Leads to complications ○ Biliary sepsis; scarring/calcified (porcelain gallbladder): higher risk for cancer PANCREATITIS Divided into 2 forms: acute and chronic, each with its own characteristic pathologic and clinical features both are initiated by injuries that lead to autodigestion of the pancreas by its own enzymes ○ Most digestive enzymes are synthesized as inactive proenzymes (zymogens) and packaged within secretory granules. ○ Proenzymes are activated by trypsin, which itself is activated by duodenal enteropeptidase (enterokinase) in the small bowel ○ Acinar and ductal cells secrete trypsin inhibitors, including serine protease inhibitor Kazal type l (SPINK1), which further limit intrapancreatic trypsin activity. Pancreatitis occurs when these protective mechanisms are disrupted or overwhelmed Acute attacks may range from mild and self-limited to life-threatening events. Recurrent or persistent pancreatitis may lead to permanent loss of pancreatic function. Pancreas function important as it secretes glucagon. ACUTE PANCREATITIS Patho: Inflammation of the pancreas ○ Autodigestion of the pancreas from enzyme activation; results from inappropriate release and activation of pancreatic enzymes that, in turn, destroy pancreatic tissue and elicit an acute inflammatory reaction. Predisposing factors ○ Biliary tract disease, hypertriglyceridemia, ethanol-associated (66%) 3 pathways: 1. Obstruction of the pancreatic duct by a stone or other cause (usually unknown) 2. Acinar cell injury 3. Defective intracellular transport of proenzymes within acinar cells.  19 3 PATHWAYS - Acute pancreatitis is characterized by reversible pancreatic parenchymal injury and inflammation and has many causes, including toxic exposures (e.g., alcohol), pancreatic duct obstruction (e.g., biliary calculi), inherited genetic defects, vascular injury, and infections. Pain associated with pancreatitis is caused by digestive enzymes being secreted into the parenchyma. Clinical manifestations ○ Steady, boring pain in epigastrium or LUQ ○ Increases in intensity ○ Severe tenderness on palpation ○ Radiates or penetrates to back ○ Nausea and vomiting ○ Abdominal distention ○ Hypoactive bowel sounds ○ Low-grade fever Diagnosis ○ Laboratory: lipase preferred test ○ Increase in amylase and lipase during first 12 hr (indicative) ○ Elevated aminotransferases, alkaline phosphatase, and bilirubin ○ Abdominal x-ray Ileus pattern; “sentinel loop”: a distended loop of small bowel in the area of the pancreas ○ CT of the abdomen Gold standard: allows remarkable detail CHRONIC PANCREATITIS Patho: ○ Presence of chronic inflammatory lesions in the pancreas ○ Key element: necrosis of exocrine parenchyma followed by fibrosis ○ Leads to calcification—obstructed flow of pancreatic juices ○ Persistence of symptoms secondary to pancreatic dysfunction over weeks and months Predisposing factors ○ ETOH consumption, idiopathic, hereditary, hyperparathyroidism (hypercalcemia), trauma  20 ○ Can progress even if alcohol consumption is stopped ○ Does not increase the risk for cancer - Chronic pancreatitis is defined as prolonged inflammation of the pancreas associated with irreversible destruction of exocrine parenchyma, fibrosis, and, in the late stages, loss of endocrine parenchyma. The most common cause of chronic pancreatitis is long-term alcohol use. - Chronic pancreatitis often follows repeated episodes of acute pancreatitis. It has been proposed that acute pancreatitis initiates a sequence of perilobular fibrosis, duct distortion, and altered secretions that, as a result of recurrent injury, leads to loss of exocrine parenchyma and fibrosis. - Chronic pancreatic injury of any cause leads to local production of inflammatory mediators that promote fibrosis and acinar cell loss. While there is overlap between the cytokines released during chronic and acute pancreatitis, fibrogenic factors tend to predominate in chronic pancreatitis. Clinical manifestations Bouts of acute pancreatitis with progressive endocrine and exocrine pancreatic dysfunction ○ Diabetes: progressive loss of pancreatic islets ○ Malabsorption: fat and vitamins A, D, E, and K ○ Weight loss: poor intake related to pain Insidious onset of steady, boring epigastric pain radiating to back (first symptom) Nausea After about 5 years of continual pain: decrease in symptoms (pain “burns out”)