quiz 4- bowel 2, liver 1, 2, 3 Flashcards
1
Q
• What is are the terms for S/L I inflammation?
A
o Enteritis: small bowel inflammation
o Colitis: large bowel inflammation
o Enterocolitis: both large and small bowel involvement
2
Q
• What can cause enterocolitis (coloenteritis)? Ssx?
A
o MC: infectious enteritis.
o Crohn’s, UC, ischemic colitis, radiation induced
o Infx: bacteria, viruses, fungi, parasites
o Ssx: freq diarrhea, w or w/o N/V, abdl pain, fever, chills, alteration of general condition.
o Dehydration
3
Q
• What microorganisms can cause acute enterocolitis?
A
o Bacteria: Salmonella, Shigella, Escherichia coli, Campylobacter etc.
o Viruses: enteroviruses, rotaviruses, Norwalk virus, adenoviruses
o Fungi: Candidiasis, esp immunosuppressed, or prolonged abx
o Parasites: Giardia
o lamblia (↑ incidence, ↓clinical manifestation), Balantidium coli, Blastocystis homnis, Cryptosporidium (diarrhea in immunosuppressed), Entamoeba histolytica (amebic dysentery, tropical)
4
Q
• What are endotoxins?
A
o associ w some g(-) bacteria
o a structural molecule of the bacteria, recognized by immune system
o usu released after lysis
5
Q
• What are Enterotoxins?
A
o protein toxin, released in intestine; chromosomally encoded exotoxins
o heat-stable, low molecular weight, water-soluble
o often cytotoxic, mostly pore-forming (mostly Cl- pores) → ↑Cl- permeability of apical membrane of intestinal mucosal cells. pores activated by ↑ cAMP or Ca2+ intracellularly. → Cl- into lumen, Na, water follow → secretory diarrhea in hrs
o ex: Staphylococcus aureus, E. coli.
6
Q
• What are exotoxins?
A
o excreted by microorganism (secreted, or released on cell lysis), cause major damage, destroy cells or disrupt normal cellular metabolism
o highly potent. Most destroyed by heating. Susceptible to Abs, but mb fatal
o Some deliver thru projections (cyto-cyto)
o Local or systemic effects
o Ex: effector proteins injected by type III secretion apparatus of Yersinia into target cells
7
Q
• What are some examples bacterial enterotoxins?
A
o Clostridium difficile
o E coli O157:H7
o Clostridium perfringens (C perfringens enterotoxin)
o Vibrio cholerae (Cholera toxin)
o Staph aureus (Staphylococcal Enterotoxin B)
o Yersinia enterocolitica
o Shigella dysenteriae (Shiga toxin)
8
Q
• What are common viral causes of enterocolitis?
A
o Mc= Norwalk virus. Aka winter vomiting. (norovirus). 90% non-bacterial GE in world, 50% all food GE in US
o Rotavirus = single most common cause of severe diarrhea in infants, children
o Noroviruses: ssRNA, non-enveloped.
9
Q
• What are common bacterial exotoxins?
A
o botulinum toxin of Clostridium botulinum
o Corynebacterium diphtheriae exotoxin, produced during life-threatening sxs of diphtheria.
10
Q
• What are some toxigenic bacteria that cause watery, but not bloody/WBC diarrhea?
A
o Staphs aureus: “picnic food poisoning”
o Bacillus cereus: food poison assoc w contaminated rice or meat from Chinese restaurants
o Vibrio (cholera and non-cholera): food poison assoc w contaminated saltwater crabs and shrimp
o Clostridium botulinum: assoc w improperly prepared home canned fruits and vegetables
o Clostridium difficile: “abx induced” enterocolitis
11
Q
• What are examples of enteric bacteria that commonly cause bloody diarrhea?
A
o Campylobacter jejunai and fetus: mc bacterial cause bloody diarrhea in US from contaminated pork, lamb, beef, milk products, water, exposure to infected household pets
o Salmonella: fecal-oral, raw milk, chicken, eggs. requires large inoculum unless immunocompromised. Mucosal invasion → exudative diarrhea. Salmonella enterotoxin → secretory diarrhea.
o Shigella: highly contagious w very small inoculum. contaminated water, milk, food supplies
o E coli: different serotypes cause diarrhea. Enteropathogenic type in nurseries up to 12 mos w fever, vomit, watery diarrhea. Enterhemorrhagic type, esp serotype 0157:H7: bovine reservoir, undercooked beef, unpasteurized milk. Comp: HUS, TTP
12
Q
• What are the stats of food poisoning in US? Causes?
A
o in 2007, 47.8 million (16%), 127,839 hospitalized, 3,037 died
o food illness: #1 norovirus, 2 Salmonella, 3 Clostridium perfringens, 4 Campylobacter
o food death: 1 Salmonella, 2 Toxoplasma gondii, 3 Listeria, 4 Norovirus
13
Q
• what is Necrotizing enterocolitis (NEC)? Etio?
A
o mostly in premature infants, or neutropenic CA pt 2nd to gut colonization
o portions of bowel undergo necrosis. MC=near ileocecal valve
o no definitive known cause. mb infx (cluster outbreaks in NICUs), no common organism identified
o mb Pseudomonas aeruginosa
14
Q
• what puts the neonate at risk for NEC?
A
o Combo of intestinal flora, inherent weak immune system, empirical abx 5+ days, alterations in mesenteric blood flow, milk feeding
o almost never seen in infants before oral feedings are initiated
o Formula feeding ↑ risk 10x compared to breast fed
o breast milk protects premature infant: Igs, also dt rapid digestion
15
Q
• what is xray finding in NEC? Gross?
A
o Pneumatosis intestinalis: gas cysts in bowel wall (not lumen)
o Gross: intestinal necrosis, pneumatosis intestinalis, perforation site
16
Q
• What is pseudomembranous enterocolitis?
A
o Often dt Clostridium difficile (st aka C. difficile colitis)
o can cause of abx-assoc diarrhea (AAD)
o foul diarrhea, fever, abd pain
o severe: life-threatening complications can develop, such as toxic megacolon
o Broad spectrum abx or immunosuppression allows overgrowth of flora (C diff, S. aureus, Candida)
17
Q
• describe gross and histo PMEC:
A
o G: Mucosa of colon is hyperemic, partially covered by a yellow-green exudate; mucosa not eroded
o H: Overlying pseudomembrane has numerous inflammatory cells, mainly Ns, necrotic epithelium, fibrin, mucus → overgrowth of microorganisms takes place
18
Q
• How is PMEC dx?
A
o First line: Stool test for C diff toxin (A and B), ↑ false (-) rate
o Also, 1) stool culture for C diff (GDH Ag), if (+) → 2) PCR for toxin genes
o Colonoscopy, sigmoidoscopy → “pseudomembranes” on colon, rectum
19
Q
• What is ischemic colitis? Cause? Ssx? Gross?
A
o Inflame, injury of LI dt inadequate blood supply
o Uncommon, but more in elderly
o Dt: change in systemic circulation (acute ↓BP dt hemorrhage) , or constriction of blood vessels, clot (local)
o Usu no specific cause identifies
o Ssx: vary, abd pain (often left), mild-mod rectal bleeding. fever N/V, diarrhea
o Pale areas, w dusky bluish appearance on colon wall (severe)
20
Q
• Which arteries specifically contribute to ischemic colitis?
A
o Weak pts, “watershed” areas, at borders of collateral vessel from sup and inf mesenteric arteries: at splenic flexure, transverse colon
o Watershed areas are most vulnerable
o Rectum has dual blood supply (inf mes a, internal iliac a) thus rarely involved in IC
21
Q
• What is radiation enteritis? Ex?
A
o Severe inflammation, neovascularization, ulceration
o Dt radiation tx
o Ex: 55 yo female, radiation after hysterectomy, BL salpingo-oophorectomy for endometrial carcinoma. Radiation=external beam, brachytherapy
o → rectal bleeding
o Sigmoidoscopy: extensive radiation proctitis
22
Q
• What are small bowel tumors?
A
o benign and malignant, relatively uncommon (compared to LI CA)
o Usu asx, or large enough to obstruct lumen, cause intussception or volvulus
o May bleed, rarely perforate
23
Q
• What are benign SI tumors? Types?
A
o well-circumscribed, smooth, small, don’t easily bleed or ulcerate, but only bx can confirm
o mb single lesions or multiple of several subtypes; rare; usu asx throughout life
o Adenocarcinoma: MC type; usu near stomach; may obstruct;
o Hyperplastic polyps
o Adenomas
o Gut stromal tumors
o Lipomas
o Hamartomas
o Hemangiomas
24
Q
• What are hyperplastic polyps of SI? Ademoas?
A
o HP: mucosal growths, duodenum, proximal ileum. single or mult. Usu asx, no malig potential
o A: 3 types: adenomatous polyps, Brunner gland adenomas, villous adenomas (rare, duodenum, bleeding, obstruction, mb malig, esp >4cm). single or mult, sessile or pedunculated. Histo: intraluminal extensions of sub/mucosa mult acini on central fibrovascular core. Varying differentiation
25
• What are gut stromal tumors? Histo? Ex?
o Benign: Aka Leiomyomas & Leiomyosarcoma
o smooth muscle; usu near LI, mb in Meckel’s, spindle cells bw muscularis propria and muscularis mucosa, may form intra/extraluminal masses, transmural lesion
o focal or annular lesions, ulceration, or deeper necrosis → bleeding, marked hemorrhage (mc complications)
o malig: diff to distinguish, 2-3x less common, depends on cell size, differentiation, mitotic bodies (>2 per 10 hpf is risk)
o histo: elongated spindle cells, w cigar-shaped nuclei, no ↑mitosis
o ex: leiomyoma at ligament or treitz (suspensory mm of duodenum)
26
• what are lipomas of SI? Histo?
o submucosal, mesenchymal origin. usu ileum/ileocecal valve, pedunculated. sessile or ependymal. Mb big enough to cause colicky abd pain, intermittent bowel obstruction, Intussusception
o mb surface ulceration, central necrosis, hemorrhage
o Histo: mature adipose w fibrous strands
27
• What are SI hemangiomas? 3 types?
o vascular tumors, 3 types: capillary, cavernous (mc), mixed
o solitary or mult, up to 10% of small bowel lesions.
o GI bleeding common. chronic (long-standing occult anemia) or profound (require massive transfusion, emergent laparotomy)
o Difficult to dx and localize sx lesions
28
• What are SI harmartomas? Ssx? Tx?
o Assoc w Peutz-Jeghers syndrome
o Focal, resemble neoplasm of tissue of origin, not malig, grows at same rate as surrounding tissue, but disorganized
o Usu asx; Colicky abd pain, GI bleeding, obstruction (usu dt intussusception)
o St Malig (2-3%) , w other non-GI CAs
o Tx: surveillance, biannual barium upper GI series, flexible endoscopy beginning at age 10
o **harmartomas also seen in stomach and LI, outside GI
29
• What are common complications w benign SI tumors, usu depending on size?
o Bowel obstruction: up to 30%, leading cause of intussusception in adults.
o Volvulus: from serosal ependymal lesions
o GI bleeding: up to 38%; occult, heme-positive stool, or acute and copious (esp large vascular lesions). may require transfusion, embolization, emergency surgery
o Perforation: → peritonitis, need emergency laparotomy
30
• what is PJS? Incidence? 2 types? Ssx?
o AD, mucocutaneous pigmentation (face, lips, buccal mucosa, hands, feet), benign GI hamartomas (90%)
o Rare: 1:25,000-300,000 births
o Familial: STK11 gene. AD
o Sporadic: not AD, unknown gene
31
• What are ssx of PJS? Dx?
o Pigmentation: oval, round, brown, black macules or spots, 1–10 mm
o Intestinal polyps (hamartomas), jejunum and ileum
o Dx: avg at 23, or identified at birth by astute pediatrician
o Often 1st presentation is bowel obstruction dt intussusception → mortality
o Before puberty: mucocutaneous lesions on palms and soles
32
• What is histo appearance of SI hamartomas?
o distinctive frond-like appearance, stromal/smooth muscle core covered by acinar glands and normal mucosa. No Nuclear atypia
o hyperplastic mucosal epithelium, arborizing pattern of smooth muscle
33
• what are other risks assoc with PJS?
o ↑ CA in multiple sites
o Hamartomas small malignant potential (<2-3%)
o ↑ risk carcinomas of pancreas, liver, lungs, breast, ovaries, uterus, testicles, other organs
34
• What are growth patterns of benign SI tumots?
o Intralumnal: assoc secondary bowel obstruction and intussusception
o Infiltrative
o Serosal: linked to small bowel volvulus
35
• What theories explain the scarcity of SI tumors, and ↓ malignant transformation?
o 1) rapid intestinal transit thru SI limits contact time to mucosa.
o 2) greater fluidity of small bowel chyme may dilute luminal irritants
o 3) alkaline pH, low bacterial colony counts
o 4) ↑ benzyl peroxidase (detox potential carcinogens)
o 5) ↑ IgA, widespread gut lymphoid tissue → impede growth, transformation
36
• What are malignant SI tumors?
o 64% of SI tumors
o 40% are adenocarcinomas
o 1st CA of SI relatively rare, 2% of all GI CAs
o MC= Adenocarcinoma, in US
o Other: carcinoid tumors, lymphomas, sarcoma aka gastrointestinal stromal tumors (GISTs)
o Often not found until metastasize, other complications
37
• What are SI adenocarcinomas?
o Similar to LI adenocardinomas, but tend to be more proximal (near stomach)
o 50% duodenum (1st to be exposed to ingested chem, pancreaticobiliary secretion, bile mb carcinogenic), 30% jejunum, 20% ileum (dt crohn’s)
o tend to co-occur in same individuals, ↑ risk in survivors of colorectal CA and vice versa.
o arise from premalignant adenomas, sporadically, or w familial adenomatous polyposis.
o Adenoma → dysplastic → carcinoma in situ → invasive adenocarcinomas
o → metastasize via lymphatics, portal circulation to liver, lung, bone, brain, other
38
• What are GISTs of SI?
o 25-30% in distal jejunum, ileum
o all regarded as potentially malignant
o 2 main criteria for degree of agressiveness: size and mitotic count per hpf
o > 5 cm w mitotic count > 5 per 50 hpf = high-risk lesions
39
• What tumors commonly metastasize to SI?
o Metastatic is mc CA in SI
o Melanomas; breast, lung, cervical adenocarcinomas; ovary, pancreas, colon, stomach
o SI is most frequent site of metastatic melanoma in GI tract dt rich blood supply
o →Metastatic lesion mb found up to 21 yrs after tx of primary tumor
o Breast and lung are unclear
40
• What are possible sxs of SI benign tumors (non-specific)?
o Abd pain: nonspecific, dull, epigastric in location, w larger lesions
o mb constipation, N/V
o diarrhea, early satiety, anorexia, hemorrhage, melena, volvulus
o Bowel obstruction, up to 30%; → intussusception in adults.
o GI bleeding, up to 38%, occult, heme-positive stool, or acute and copious,
o perforation into peritoneal cavity, uncommon
41
• what is epidemiology of SI CAs? Px?
o Slightly higher in blacks than whites, mb 2x
o M>F, 1.4:1
o Avg 60
o 30-35% 5-yr survival for adenocarcinomas, 2%% for sarcomas
42
• What are carcinoid tumors of SI?
o 29%-40% of 1st SI cancers, incidence rising in US
o Arise from neuroendocrine cells
o Mostly ileum, within 60 cm of ileocecal valve.
o < 1 cm 15% risk metastasis at time of dx
o > 2 cm 50%.
o Metastasis targets: liver, lungs, bones.
o Carcinoid syndrome: excess 5-HT
43
• What is appearance of SI carcinoid tumors?
o Gross: at ileocecal valve, smooth, well circumscribed
o Mb submucosal or extend into lumen
o Histo: endocrine appearance, collections of small round cells, nuclei consistent in size and shape
44
• What is a colorectal polyp?
```
o fleshy growth in lining
o benign (hyperplastic polyp), pre-malignant (tubular adenoma), malignant (colorectal adenocarcinoma)
o untx: potentially develop into colorectal cancer
```
45
• what are hyperplastic colorectal polyps?
o MC colorectal polyps, usu benign, < 1/4 in
o Hyperplastic= ↑ # cells; normal differentiation and maturation
o “rice grains” on colonic mucosa
o In lower part of crypt, cells become more crowded and hyperchromatic
o Usu descending colon and rectum of elderly
o Looks like adenomatous polyp
46
• What arte tubular adenomas?
o aka adenomatous polyp
o rounded neoplastic glands, smooth surfaces, discreet
o common in adults
o Small ones are virtually always benign
o > 2 cm ↑ risk carcinoma, dt APC, DCC, K-ras, p53
47
• What is histo and gross appearance of a benign adenomatous polyp?
o On stalk; glands more irregular, crowded, rounded; darker/hyperchromatic and more crowded nuclei
o ↓ goblet cells
o Benign: well-differentiated, closely resembles normal colonic structure.
o Gross: hemorrhagic surface (mb initially detected by stool occult blood screen), long narrow stalk. If > 2 cm, ↑ risk malig
48
• What are the benign tumors of LI?
o adenomas, leiomyomas, fibromas, neurofibromas, lipomas, carcinoid tumors
49
• what are villous adenomas? Appearance?
o Less common than adenomatous polyps; more likely to have invasive carcinoma (40%)
o Gross: sessile, not pedunculated, larger than tubular adenoma
o Usu several cm in diameter, up to 10cm long
o Micro: cauliflower-like appearance, dt elongated glandular structures covered by dysplastic epithelium
50
• What is Juvenile polyposis syndrome?
o mult polyps in GI tract, usu child, adolescent, young adult
o “juvenile”= histological type, not age (age is variable)
o mostly non-neoplastic, hamartomatous, self-limiting, benign
o but ↑ risk adenocarcinoma (9-50% lifetime risk)
o ssx: rectal bleeding, abdominal pain, diarrhea, anemia
o colonoscopy or sigmoidoscopy: various size and shaped polyps, sessile or pedunculated
51
• what is micro appearance of JPS?
o characteristic inflamed, edematous stroma; eroded surface and cystic epithelial elements.
o Mb dysplasia or not, but usu large and multi-lobulated polyps should be carefully evaluated for neoplastic changes
o Epithelial surface maturation differentiates reactive/reparative change from dysplastic change.
52
• What is Familial adenomatous polyposis (FAP)?
o AD, hundreds to thousands of polyps in LI epithelium (early adolescence)
o Mb risk of other malignancies (duodenum, stomach)
o start benign → malignant transformation into colon adenocarcinoma if untx (100% lifetime risk)
53
• What are ssx of FAP? Imaging? Tx?
o ssx: mb bleed, IDA
o if malig: weight loss, altered bowel habit, or metastasic to liver, etc
o sigmoidoscopy: carpet of small adenomatous polyps.
o Tx: total colectomy, by 20
54
• what is garner’s syndrome? Ssx? Work-up
o AD. =FAP + combo of polyposis, osteomas/osteomata (benign bone tumors), fibromas, sebaceous cysts
o Add’l ssx: “CHRPE - congenital hypertrophy of retinal pigment epithelium", jaw cysts, , epidermal inclusion cysts
o Need xrays; mb osteomas in long bone
o early age: subtle defects in mandible; Eye exams detect pigmented lesions of retinal fundus.
o Colonoscopy and other invasive tests to check for polyps every 1-2 yrs
55
• What is gross appearance of LI adenocarcinoma? Micro?
o May arise from villous adenoma
o Gross: surface is polypoid, reddish pink. mb large ulcer w tumor lesion. Hemorrhage from surface → guaiac positive stool; ulcer suggests CA; encircling mass common in descending colon
o micro: may see edge of carcinoma arising in villous adenoma. neoplastic glands are long and frond-like (like villous adenoma). primarily exophytic (outward into lumen); mb some differentiation (w irregular, crowded glands, nuclei, hyperchromatic, pleomorphic, mb no normal goblet cells), lumens w mucin
56
• what are ssx of LI adenocarcinoma? Staging?
```
o Ssx: change in stool or bowel habits mb dt mass effect of tumor
o Staging (dukes): based on degree of invasion into and through wall
```
57
• what is Dukes staging system?
o For colon CA, 4 categories
o A: Tumor is only as deep as mucosa
o B1: in muscularis propria
o B2: through muscularis propria.
o C1: to muscularis propria and LNs, positive for CA
o C2: through muscularis propria and LNs, positive for CA
o D: outside intestine, mb spread to nearby organs
58
• What is histo appearance of a leiomyosarcoma?
o leiomyoma can be differentiated from leiomyosarcoma; both have ↑ cellularity
o leiomyosarcomas: ↑cell density, more mitotically active (> 2)
59
• what is histo appearance of GI lymphoma?
o large blue non-Hodgkin's lymphoma cells, infiltrating thru mucosa
o prominent clumped chromatin and nucleoli w occasional mitotic bodies
60
• What is the liver?
o largest visceral gland in body (3 lbs, 1200-1600g); red-brown, smooth surface; 4 lobes → 1000s of lobules
o blood supply by hepatic a (O2) and portal v (nutrients)
o only internal organ capable of signifigant regeneration, only 25% needed to totally regenerate
o dt hepatocytes are unipotent stem cells → quiescent (G0) hepatocytes can reenter cell cycle (G1) → mitosis
o think Prometheus getting his liver eaten every day by vulture, regenerating
61
• What is the role of the liver?
o main detox organ of endogenous and exogenous substances
o metabolism of carbohydrates, proteins fats
o produces bile, alkaline, digestion, emulsification of lipids
o produces coagulation factors (I, II, V, VII, IX, X, XI, C, S, AT)
o storage: glucose (glycogen), vit B12, iron, copper
o RES has immunologically active cells, 'sieve' for Ags via portal system
62
• Describe the role of the fetal liver:
o 1st tri: main site of RBC production
| o 32nd wk: BM almost completely takes over
63
• What are the major primary diseases of the liver?
```
o Viral hepatitis
o Non-viral hepatitis
o Alcoholic liver disease
o Non-alcoholic fatty liver
o Hepatocellular carcinoma
```
64
• What are general features of liver dz?
o Generally, slow, insidious, sxs weeks, months, years after injury onset (except fulminant hepatic failure)
o Mb long time bw onset and dx, and liver mb injured and heal wo clinical detection
o Many: jaundice dt ↑ bilirubin, breakup of the hemoglobin of dead RBCs. Normally, liver removes bilirubin from blood and excretes it via bile
65
• What is incidence of liver dz in US? Causes?
```
o ~75/100,000 new dx of chronic each year; 44,000 deaths per year (1.9%, 8th, bw diabetes and suicide)
o 57% hepatitis C
o 24% alcohol-induced liver dz
o 9% nonalcoholic fatty liver dz
o 4% hepatitis B
```
66
• What are the general responses of liver to disease, regardless of cause?
```
o Degeneration and intracellular accumulation
o Necrosis and apoptosis
o Inflammation
o Regeneration
o Fibrosis
```
67
• What is degeneration and intracellular accumulation of the liver?
o Damage from toxic or immunologic insult → swelling of hepatocytes
o Moderate cell swelling is reversible.
o more severe (ballooning degeneration), swollen hepatocytes have irregularly clumped cytoplasmic organelles and large clear spaces → may not be reversible
o Substances may accumulate in viable hepatocytes → reduce cellular function, or cell death (iron, copper (Wilson’s dz), fat, etc)
68
• What is iron deposition/overload in liver dz?
o = hemochromatosis
o Micro: hepatocytes and Kupffer cells full of granular brown deposits of hemosiderin dt accumulation of excess iron in liver
69
• What is steatosis in liver dz?
o accumulation of triglyceride fat droplets in hepatocytes
o mc cause in developed nations is alcoholism
o developing: kwashiorkor in children
o other: DM, obesity, severe GI malabsorption
o micro: lipid vacuoles in hepatocytes. clear on H&E
70
• describe histology of liver degeneration dt acute hepatitis?
o large pink cells undergoing "ballooning degeneration"
| o later stage: dying hepatocyte seen shrinking down to form an eosinophilic “Councilman body"
71
• what happens with necrosis and apoptosis with liver dz? Histo?
o Any significant insult to liver can cause hepatocyte necrosis
o ischemic coagulative necrosis: hepatocytes poorly stained, lysed nuclei
o apoptotic: hepatocytes coalesce to form shrunken, intensely eosinophilic staining cells w fragmented nuclei = “Councilman hyalin bodies”; seen in many dzs
o Hepatocytes may also osmotically swell and rupture = lytic necrosis
72
• What happens with inflammation with liver dz?
o =hepatitis: influx of acute or chronic inflammatory cells
o Direct toxic or ischemic hepatocyte necrosis incites inflammatory rxn
o Destruction of ag-expressing liver cells by cytotoxic lymphocytes is common mechanisn (esp viral inx)
o Mc types of liver dz, and are often long-term chronic
73
• What happens in viral hepatitis?
o quiescent lymphocytes collect in portal tracts = inflammation
o →migrate into specific areas of periportal parenchyma as activated lymphocytes
o →moderately active hepatitis when inflammatory process is more localized; or severe if more diffuse
74
• how is hepatic apoptosis related to inflammation in liver dz?
o Identification of apoptotic hepatocytes is a sign of very recent hepatocyte destruction
o Once killed, apoptotic hepatocytes don’t usu incite diffuse inflam rxn
o But scavenger M0s (Kupffer cells) engulf apoptotic fragments in few hrs →localized clumps of inflame cells → activates cytokine cascade
75
• What is gross appearance of hepatitis? Micro?
o Gross: areas of necrosis and collapse of liver lobules, seen as ill-defined areas, pale yellow
o Micro: mononuclear inflammatory cell infiltrate extends from portal areas and disrupts limiting plate of hepatocytes undergoing necrosis, = "piecemeal" necrosis of chronic active hepatitis. If dt hep B: HbsAg and HbcAb positive
76
• When do hepatocytes regenerate?
o have long life spans, proliferate in response to tissue resection or cell death
o Regeneration occurs in all but the most fulminant hepatic dzs
o marked by mitoses, thickening of hepatocyte cords, disorganization of parenchyma
77
• why does fibrosis occur in liver dz? Consequences?
o in response to inflammation or direct toxic insult
o fibrosis and cirrhosis →generally irreversible damage
o Deposition of collagen affects hepatic blood flow and perfusion of hepatocytes
o → liver is subdivided into nodules of proliferating hepatocytes surrounded by scar tissue (cirrhosis)
78
• What causes nodular cirrhosis? gross appearance?
o Ongoing liver damage w necrosis → fibrosis and hepatocyte regeneration → cirrhosis
o →nodular, firm liver. Nodules > 3 mm, "macronodular" cirrhosis.
o micronodular cirrhosis: w fatty change, small, yellow nodules. Mb w Wilson's dz, primary biliary cirrhosis, hemochromatosis
79
• what is micro appearance of cirrhosis?
o regenerative nodules of hepatocytes are surrounded by fibrous CT that bridges bw portal tracts
80
• What are infx inflammatory liver dzs?
o infx mc type of hepatitis
o usu blood borne infxs, whether systemic or arising in abdomen
o viral mc and notable
o others: TB, malaria, staphylococcal bacteremia, salmonella, candida, amebiasis
81
• what is “viral hepatitis”?
o dt “hepatotropic” viruses, affinity for liver, ability to replicate in hepatocytes
o mc= hepatitis A, B, C, D, E viruses
o other: EBV (mono) may cause mild hepatitis during acute phase, CMV (newborns, immunosuppressed), Yellow fever virus (tropical countries)
82
• what is hep A virus?
o benign, self-limited, inc 2-6 wks; 25% acute hepatitis worldwide; 270,000/yr new dx in US
o doesn’t cause chronic hepatitis or a carrier state; rarely causes fulminant hepatitis; fatality ~0.1%
o more severe if it is superimposed on chronic HBV, HCV, alcohol hepatitis
o endemic w ↓ hygiene (seen in kids)
83
• what are ssx of hep A? markers for dx?
o 1-2 wks incubation (viremia) → mild or asx, mb febrile, N/V
o at sx onset (1-2 wks): ant-HAV IgM appears in blood, reliable marker of acute infx; also ↑ALT
o Fecal shedding of virus (also dx method) ends as IgM titer rises
o IgM declines in ~3 mos → IgG anti-HAV, persists for years, or life, against reinfection by all strains of HAV= immunity (same response with HAV vaccines)
84
• What are types/outcomes of Hep B infx?
o (1) acute hepatitis with resolution, (2) chronic hepatitis, may → cirrhosis, (3) fulminant hepatitis w massive liver necrosis, (4) backdrop for hep D infx
o Pts w chronic hepatitis = carriers of actively replicating virus =infectious to others
85
• What is incidence/epidemiology of hep B?
o worldwide carrier rate of 350 million
o has infected over 2 billion ppl alive today at some point in their lives
o 75% of all chronic carriers in Asia, Western Pacific rim
o global prevalence: high (>8%) in Africa, Asia, Western Pacific; intermediate (2-7%) in S & E Europe; low (<2%) in Western Europe, North America, Australia
o US: 185,000 new infxs per yr
86
• What happens with chronic hep B infx?
o prolonged incubation (4-26 wks). remains in blood up to and during active episodes of acute and chronic hepatitis
o present in all physiologic and pathologic body fluids (except stool)
o important role in the development of hepatocellular carcinoma
87
• how is hep B spread?
o hardy virus can withstand extreme temperature and humidity
o blood and body fluids are primary vehicles of transmission
o also contact w semen, saliva, sweat, tears, breast milk, pathologic effusions
o risks: Transfusion, blood products, dialysis, needle-sticks in health workers, IV drugs, sexual activity
o unknown source in 1/3
o endemic (Africa, SE Asia): vertical transmission is common (20-60% births to infx moms)→ carrier state for life
88
• what is prevalence of hep C?
o 40,000 new dx per yr in US (150,000 in 1980s)
o 1.8% in US (3.9 million) have anti-HCV Abs (2% in 1990s); 70% (2.7 million), have chronic infx (serum viral DNA)
o MC chronic blood-borne infx in US, almost half of all pts w chronic liver dz
o major cause of liver dz worldwide
o total # chronic projected to ↑ 4x from 1990-2015, so prevalence is still increasing
89
• how is hep C spread?
o Major: inoculations and blood transfusions
o IV drugs: 60%
o Sexual transmission 15% (presumably), althoufh risk considered to be low (12 events per 1000 person-yrs in sexual partners of HCV-infx pts).
o transfusions prior to 1991 10%, hemodialysis pts and health care workers < 5%
o perinatal: ↑, 6% of births to infx mothers
o highest populations: house hold contacts, homosexual males, hemodialysis pts, hemophiliacs, IV drug abusers
90
• how is hep C dx? Px?
o anti-HCV Ab in > 50% of unexplained cirrhosis
o Acute HCV infection generally undetected clinically
o progression to chronic in majority
o Cirrhosis eventually in ~20% w chronic
o =potential to become leading cause of chronic liver dz in Western world
91
• What is clinical course of acute hep C?
o incubation 2-26 wks, HCV RNA detectable in blood for 1-3 wks, and ↑ serum transaminases
o acute symptomatic: anti-HCV Abs detected in only 50-70%s; others, antibodies see after 3-6 wks
o clinical course of acute usu milder than HBV; Less commonly, mb severe and indistinguishable from HAV or HBV hepatitis
92
• what is clinical course of chronic HCV?
o Serum HCV RNA persists in >90% despite neutralizing Abs
o Symptomatic: dx by serum HCV Ag and Ab tests
o Characteristic, episodic ↑ serum aminotransferases, bw normal periods
o Also serum Viral counts
93
• What is HDV? How does infx occur?
o Aka "hepatitis delta virus,“ unique RNA virus, replication defective, causing infx only when encapsulated by HBsAg
o dependent on HBV genes for multiplication, causes hepatitis only in presence of HBV
o Acute co-infection after exposure to serum w both HDV and HBV
o HBV must become established first to provide HBsAg
o Supra-infx: Chronic HBV carrier + new HDV exposure → dz about 30-50 days later (usu more severe than HBV alone)
94
• What is prevalence of HDV? How is it spread? Outcome?
o Mostly in Mediterranean, Middle East, northern Africa
o uncommon in US except in IV drug abusers and hemophiliacs (or need lots of blood)
o Once infected, spread by sharing needles or sexual contact
o HBV becomes more virulent w HDV, may → fulminant liver necrosis, death
95
• What is HEV?
o Acute, ssx usu resolve in 6 wks
| o Wxcept of preg: may → fulminant hepatic necrosis, fatality15-25%
96
• What is HGV?
o 1-2% of blood donors, no known pathogenic activity
| o Also in sera of Hep C pts = “innocent bystander” virus.
97
• What is chronic hepatitis? Causes?
o = symptomatic, biochemical, or serologic evidence of hepatic dz > 6 mos, w histo inflammation and necrosis
o =carrier state, replicating virus which can be transmitted(sx/clinical picture varies)
o Often dt Hep B, C, B+D, also many other non-contagious causes: chronic alcoholism, Wilson’s, alpha 1 -antitrypsin def, drugs, hepatotoxins, AI
o etiology is most important indicator of likelihood to progress to cirrhosis
98
• what happens to structure of liver in chronic hepatitis?
o Mild: sig inflam limited to portal tracts; lymphocytes, M0s, some plasma cells, rare Ns, Es
o architecture usu well preserved, but mb individual hepatocyte necrosis
99
• what is histo appearance of C and B chronic hepatitis?
o Hep C: inflammatory cells, bands of fibrous tissue stain blue
o Hep B: “ground glass hepatocyte”= diffuse granular cytoplasm, characteristic hazy, eosinophilic staining cyto, dt abundant HBsAg in ER; also in some drug induced causes; not in acute
100
• What is cirrhosis liver dz? Pathophysiology?
o hallmark of irreversible liver damage = deposition of fibrous tissue
o initially portal tracts → periportal septal fibrosis → linking of fibrous septa bw lobules (bridging fibrosis)
o loss of hepatocytes, eventually → cirrhosis, w fibrous septae and hepatocyte regenerative nodules, large irregular size, separated by scars
o gross: coarse nodular surface
101
• what can cause cirrhosis?
o AI hepatitis, hepatotoxins (CCl4, mushrooms), drugs (acetaminophen), alcohol, Hep C, B+D
o st unknown etio at autopsy= morphology of end-stage cirrhosis may not point to cause of injury
102
• what is fulminant hepatitis? Causes?
o When hepatic insufficiency progresses from onset of sxs to hepatic encephalopathy in2-3 wks
o 12% dt viral hepatitis in US, usu HBV
o Mb HAV infx or non-hepatotropic virus (HSV) may reactivate latent HBV infx → fulminant
o 50% dt Drug, chemical toxicity; direct hepatotoxins or via 2nd inflam rxns; ACETOMINOPHEN, Isoniazid, Halothane, Methyldopa
o exposure to the mycotoxins of mushroom Amanita phalloides
o 18% unknown
103
• What happens to the liver in fulminant hepatitis? Appearance?
o entire liver mb involved or only random areas; mb little or lots of inflam rxn, more phagocytes with time to clean up necrosis
o w massive loss of tissue → shrink to 500-700g → limp, red organ covered w wrinkled, too-large capsule
o gross: necrotic areas are muddy red, mushy, blotchy bile staining (green)
o micro: complete destruction of hepatocytes in contiguous lobules →collapsed reticulin framework and preserved portal tract
104
• What is px of fulminant hepatitis? Pathophysiology?
o If survive past 1 wk → 2nd regeneration of surviving hepatocytes and bile ducts
o Past first few wks →potentially recover completely to normal
o W centrilobular zonal necrosis dt direct hepatotoxins or ischemia, parenchymal framework is preserved → regeneration → architecture restored
o massive lobule destruction → regeneration is disorderly → nodular, irregular after healing
105
• how do alcohol and acetaminophen(APAP) injure the liver?
o Alcohol-induced impaired hepatic metabolism of methionine → ↓ intrahepatic glutathione → ↑ oxidative injury
o Induction of CYP ↑ alcohol metabolism in ER, ↑ conversion of APAP to toxic metabolites, especially N-acetyl-p-benzoquinone-imine (NAPQI)
106
• What is acetominophen (APAP) overdose? Pathophysiology?
o >7g/24 hrs, or taken with alcohol → severe hepatic necrosis → liver failure, coma, death
o as low as 4g/24 hrs, esp w alcohol
o APAP is oxidatively metabolized in the liver via P450 (→ROS, damaging) to NAPQI. Overdose when this pathway is saturated
o NAPQI has short half-life, normally rapidly conjugated w GSH (SH donor), excreted in urine
o excessive NAPQI formation or w ↓GSH stores, NAPQI covalently binds to vital proteins and lipid bilayer of hepatocyte membranes →hepatocellular death, liver necrosis
107
• what is the clinical course of APAP poisoning? Histo?
o Stage 1: 12-24 hrs, N/V
o Stage 2: 24-48 hrs, mb improved, but ↑AST, ALT, Bilirubin
o Stage 3: 72-96 hrs, peak hepatotoxicity, AST may exceed 20,000
o Stage 4: >96 hrs, recovery, liver transplant, or death
o Histo: extensive hepatocyte necrosis, some dead or dying. Seen w a variety of hepatotoxins
108
• What is the antidote for APAP poisoning?
o n-acetyl-cysteine (NAC) =precursor of GSH, increases GSH availability to bind to NAPQI.
o enhance sulfate conjugation of any unmetabolized APAP
o =anti-inflam and antioxidant
o increases local NO concentrations →vasodilation, ↑local oxygen delivery to peripheral tissues; ↓morbidity and mortality, even after hepatotoxicity, or late fulminant wo measurable serum APAP
o most effective within 8 hrs of ingestion, but given regardless
o Therapy with NAC has been shown to decrease mortality rates in late-presenting patients with fulminant hepatic failure
109
• What is Alcoholic liver dz? Alcohol stats?
o =Hepatic steatosis, alcoholic hepatitis, cirrhosis
o A maladaptive state, hepatocytes respond in increasingly pathologic manner to alcohol, that originally was only marginally harmful
o Excessive alcohol (ethanol) consumption, leading cause of liver dz in most Western countries
o ~40% of deaths from cirrhosis dt alcohol-induced liver dz
o Alcohol abuse causes 200,000 deaths annually, 5th leading cause of death, many related to MVA
o 67% of 18+ drink alcohol. Some →serious health consequences dt alcoholism
110
• What happens to alcohol in the body? Consequences?
o a solute at mM concentrations, directly affects microtubular, mitochondrial fxn, membrane fluidity
o alcohol →acetaldehyde (AA) →acetate
o AA induces lipid peroxidation, oxidative damage
o Alcohol-induced and AA-induced changes in hepatocellular proteins →inflam/immune hepatocellular injury
o ↑Endothelins, potent vasoconstrictors →myofibroblast-like perisinusoidal stellate cells → ↓hepatic sinusoidal perfusion, hypoxia
111
• What is Hepatic steatosis (fatty liver)?
o After moderate intake of alcohol, small (microvesicular) lipid droplets accumulate in hepatocytes
o Or short-term ingestion of up to 80g (8 beers or 7 oz 80-proof liquor) in 1-7 d →reversible
o Chronic, lipid accumulates when Lp transport disrupted or FAs accum
o Alcohol interferes w mitochondrial and microsomal fxn in hepatocytes →accumulation of lipid.
112
• Describe histology of hepatic steatosis?
o macrovesicular steatosis: involves most regions of lobule. intracytoplasmic fat seen as clear vacuoles. Some early fibrosis (stained blue)
o large, clear macrovesicular globules, compress and displace nucleus to periphery
113
• describe gross appearance of hepatic steatosis? Outcomes?
o Large liver (up to 4-6 kg), soft, yellow, greasy (both capsule and inside)
o little or no fibrosis at outset, but continued alcohol intake → fibrous tissue around terminal hepatic veins, into adjacent sinusoids
o completely reversible at this point if quit alcohol
114
• what is alcoholic hepatitis?
o Hepatocyte swelling (ballooning) and necrosis, single or scattered foci of cells
o swelling dt accumulation of fat, water, proteins that are normally exported
o st mild deposition of hemosiderin in hepatocytes and Kupffer cells
o Mallory body inclusions seen
o Ns permeate lobule, accumulate around degenerating hepatocytes, esp w Mallory bodies
o Ls and M0s also enter portal tracts, spill into liver parenchyma
115
• What are Mallory bodies?
o characteristic but not specific feature of alcoholic liver dz
o accumulation of keratin, other proteins →visible as eosinophilic cytoplasmic inclusions
o globular red hyaline material in hepatocytes =Mallory's hyaline, aka "alcoholic"= aggregates of intermediate filaments in cytoplasm dt hepatocyte injury
o surrounded by fibrous tissue
o mb seen w NASH, primary biliary cirrhosis, Wilson’s, hepatocellular tumors
116
• what happens with chronic alcoholic hepatitis?
o almost always w fibroblast activity → fibrosis
| o fibrotic bands usu means irreversible stage of dz process
117
• what is alcoholic cirrhosis?
o Final, irreversible form of alcoholic liver dz, slow, insidious
o At first, cirrhotic liver is fatty, yellow-tan, enlarged, > 2 kg
o Over yrs, → shrunken, non-fatty organ, < 1 kg, brownish green
o develops more rapidly w severe alcoholic hepatitis, in 1-2 yrs
118
• what is pathophysiology of alcoholic cirrhosis?
o Initially, fibrous bands are delicate, extend thru sinusoids from central to portal regions, bw portal tracts
o → uniform "micronodules" from regeneration
o w time, nodularity more prominent →scattered larger nodules, “lumpy bumpy" surface
o fibrous septae dissect and surround nodules → more fibrotic, lose fat, shrinks
o Parenchymal islands engulfed by wider bands of fibrous tissue → mixed micronodular and macronodular pattern
o Ischemic necrosis and fibrous obliteration of nodules → broad, tough, pale scars
o Bile stasis often develops (Mallory bodies only rarely evident at this stage)
119
• What does end-stage alcoholic cirrhosis resemble?
o both macroscopically and microscopically, the appearance of cirrhosis dt viral hepatitis, other chronic causes
120
• what is macro appearance of alcoholic cirrhosis? Micro?
o characteristic diffuse nodularity of surface dt nodular regeneration and scarring
o greenish tint of some nodules dt bile stasis
o mb hepatocellular carcinoma, budding mass
o micro: nodules of varying sizes entrapped in blue-staining fibrous tissue. liver capsule at top
121
• what causes alcoholic cirrhosis?
o Daily intake of 80g+ ethanol = significant risk
o 160g+ for 10-20 yrs assoc w severe injury
o Only 10-15% alcoholics develop cirrhosis.
o Women more susceptible, mb dt ↓gastric metabolism of ethanol, differences in body mass
o Individual, possibly genetic, susceptibility must exist; genetic polymorphisms in detox enzymes and cytokine promoters. no reliable genetic markers identified
o may develop wo previous evidence of steatosis or alcoholic hepatitis
o thus, no "safe" upper limit for alcohol consumption can be proposed (despite popularity of red wines for CVD)
122
• what are ssx/outcomes of alcoholic steatosis?
o Mb HM w mild ↑ serum bilirubin, ALP
o Mb no clinical or biochemical evidence of liver dz
o Severe hepatic dysfunction is unusual.
o Alcohol withdrawal and adequate diet are sufficient tx
123
• what are ssx/outcomes of alcoholic hepatitis?
o St w steatsosis, too: malaise, anorexia, wt loss, upper abd discomfort, tender HM, ↑bilirubin, ALP, neutrophilic leukocytosis
o appears acutely, usu after bout of heavy drinking
o sxs and labs mb minimal, or like fulminant hepatic failure
124
• when does alcoholic hepatitis turn into cirrhosis? Px?
o W repeated bouts of acute alcoholic hepatitis, appears in 1/3 pts in few yrs
o Alcoholic hepatitis also mb superimposed on established cirrhosis
o W proper nutrition and total cessation of alcohol, alcoholic hepatitis may clear slowly; st it persists anyway → cirrhosis
125
• What are ssx of alcoholic cirrhosis?
o Like other forms of cirrhosis (jaundice)
o Usu first signs dt complications of portal hypertension → life-threatening variceal hemorrhage (esophageal, gastric), SM (500-1000g, N=<300)
o non-specific sxs: malaise, weakness, wt loss, anorexia →jaundice, ascites, peripheral edema (latter dt impaired albumin synthesis)
o stigmata: grossly distended abdomen, wasted extremities, caput medusa, often indicate end-stage
o Hepatic encephalopathy: CNS dysfxn, w LIVER FAILURE, including portal-systemic shunts. lethargy and confusion (→ coma), asterixis, nystagmus, brisk oculovestibular reflexes, decorticate and decerebrate posturing, muscle spasticity, BL extensor plantar reflexes (Babinski)
o mb clinically silent, discovered only at autopsy; or stress/infx/trauma tips balance toward hepatic insufficiency.
126
• What do gastric varices look like? Esophageal?
o G: Typical mottled, "alligator-skin"-like mucosa in gastric fundus and body
o St like gastritis grossly, but bx usu have vascular congestion wo sig inflame
o E: Bulging submucosal veins, intact veins have raised shiny smooth surface. hemorrhage has flat dark red-black appearance.
127
• What are lab findings with alcoholic cirrhosis?
o liver bx, 10-20% of presumed alcoholic cirrhosis dt another disease process
o ↑ aminotransferase, bilirubin, variable ↑ ALP, hypoproteinemia (globulins, albumin, clotting factors), anemia
128
• What is end stage alcoholic liver dz?
o long-term outlook for alcoholics w liver dz is variable
o 5-yr survival ~90% in abstainers who are free of jaundice, ascites, hematemesis
o drops to 50-60% if continue alcohol
o end-stage, causes of death:(1) hepatic coma, (2) massive GI bleed (3) concurrent infection, (4) hepatorenal syndrome after bout of alcoholic hepatitis (5) hepatocellular carcinoma (3-6%)
129
• What is Nonalcoholic fatty liver disease (NAFLD)?
o resembles alcohol induced liver dz
o M=F, obesity, dyslipidemia, hyperinsulinemia, insulin resistance, type 2 diabetes.
o Usu no inflam rxn, unless fatty cells rupture
o No hepatocyte death, scarring (despite persistent ↑LFTs)
130
• What are most common causes of fatty liver?
o ALCOHOL mc
o Toxic, metabolic, hypoxic conditions
o Malnutrition: protein deficiency, starvation, diabetes, obesity, Reye’s syndrome, fatty liver of pregnancy, tetracycline toxicity
o often assoc w metabolic syndrome
131
• What is pathogenesis of fatty liver?
o liver = principle organ of fat metabolism and synthesis
o dt Interfere w mobilizing triglycerides out of liver
o when toxins affect mito and microsomal fxns → defective oxidation of fatty acids, aberrant mito fxn
132
• how does fatty liver present clinically?
o HM mb only sign, st absent
o Early: LFTs often normal, or minmin abn
o Later: fat accumulates →LFTs begin to ↑
133
• What is gross appearance of a fatty liver? Micro?
o Gross: sever: enlarged, yellow, smooth, firm, greasy. Less sever: pale, yellow, or blotchy
o Micro: 2 types: microvesicular and macrovesicular. Hepatocytes generally normal polygonal, normal N:C, w “empty” fat bw them
o Micro: manytiny fat vesicles, requires fat stain to see; toxic condition may →hepatocellular failure
o Macro: a few large clear vacuoles in hepatocyte cytoplasm, push nucleus aside. Usu no effect, asx
134
• How is NAFLD diagnosed?
o Dx of exclusion (esp of alcoholism)
o presumed to be most likely explanation for ↑ ALT, AST, or GGT, in 24% US pop
o usu ALT>AST (AST:ALT ratio < 1)
o Liver bx: usu steatosis
135
• What is prevalence of NAFLD in US?
o ~31% M, ~16% F
| o = ~31 million Americans
136
• What are dx criteria for metabolic syndrome?
```
o Abd obesity: Waist circumference > 102cm in M, > 88 in F
o Hypertriglyceridemia (>/= 150 mg/dL)
o ↓HDL: M < 40 mg/dL, F < 50
o ↑ BP (>/= 130/85 mm Hg)
o ↑ FG: (>/= 110 mg/dL)
```
137
• What are possible risks of NAFLD? Tx?
o Up to 70% of chronic hepatitis of "unknown cause”
o contributes to progression of other liver dzs (HCV)
o unclear assoc w hepatocellular carcinoma
138
• what is tx for NAFLD?
```
o starting pt for tx: Lifestyle modifications, esp diet, exercise
o Gradual weight loss
o Vitamin E
o Taurine
o Ursodeoxycholic acid
o Troglitazone
o Metformin
o Betaine
o Lecithin
o Selenium
```
139
• what is Nonalcoholic steatohepatitis (NASH)? Complication?
o intermediate form of liver damage
o ~ 2 to 5% of Americans
o Cirrhosis, dt yrs of subclinical progression of inflam and fibrosis
140
• How is NASH diagnosed?
o suspect w ↑LFTs, no other apparent reason for liver dz (alcohol, liver toxic meds, viral hepatitis)
o Liver bx: steatosis, multifocal parenchymal inflam, Mallory hyaline bodies (like alcoholic hepatitis), hepatocyte death (both ballooning degeneration and apoptosis), sinusoidal fibrosis
141
• What is hemochromatosis? 2 types?
o excessive accumulation of body iron, usu deposited in parenchymal organs (liver); also heart (→CHF)), pancreas (→DM), joints (arthritis), skin
o Primary: Hereditary hemochromatosis (HHC), AR, excessive iron absorption in gut. mutation of hemochromatosis gene (HFE). 1:200-500 in US. 1:10 of N Euro descent have mutation (usu on C282Y, inked to MHC complex, possible HLA assoc)
o Secondary: excessive iron intake (usu mult blood transfusions)
142
• How much iron is seen in hemochromatosis? Epidemiology? Ssx? Tx?
o Normal iron store in adults is 2-6g → 50x higher
o 1:200 are hets, M>F (only after menopause)
o Untx: cirrhosis or hepatocellular carcinoma complicating cirrhosis or cardiac dysfunction
o Tx: iron chelators to remove it
143
• What is gross appearance of hemochromatosis of liver? Micro?
o Gross: Initially enlarged, rust-brown color. Later, fibrous septae and regenerative nodules typical of cirrhosis
o Micro: Initially brown pigment in periportal cells; Prussian blue iron stain: characteristic bluish pigmentation of these cells; normal parenchymal architecture is maintained; later: Fibrin bands suggest early cirrhosis
o Since iron accumulates only in hepatocytes, Kupfer and endothelial cells not affected
144
• What are ssx of hemochromatosis?
o HM, DM, pigmentation of skin (classic triad); abd pain, cardiac arrythmias, cardiomyopathy, arthritis, hypogonadism
o “bronze diabetes”: some have iron deposition in skin in conjunction w DM
145
• What is Wilson’s dz?
o AR, accum toxic levels copper in many tissues and organs, esp liver, brain eyes
o Liver mc: hepatic changes, minor to massive damage
146
• What is normal copper absorption and metabolism?
o 40-60% from diet (2-5 mg daily) absorbed in stomach, duodenum → liver
o total body copper only ~50-150 mg
o Free Cu taken up into hepatocytes, incorporated into α2-globulin in ER → ceruloplasmin (metallothionein, 90-95% of plasma Cu), resecreted into plasma
o Circulating ceruloplasmin broken down, normal plasma protein aging
o breakdown products endocytosed by liver, degraded in lysosomes, Cu normally excreted into bile (primary route for Cu elimination)
147
• what are liver changes w Wilson’s dz?
o Fatty change: mild-mod, with vacuolated nuclei, occasional focal hepatocyte necrosis
o acute hepatitis: like acute viral hepatitis, w fatty change, ↑ Cu
o chronic hepatitis: mod-sev inflame, hepatocyte necrosis, macrovesicular steatosis, vacuolated hepatocellular nuclei, Mallory bodies, ↑Cu
o With progression of chronic hepatitis, cirrhosis will often develop
148
• What are extra-hepatic manifestations of Wilson’s dz?
o Brain: Cu in basal ganglia, putamen, atrophy, cavitation
| o Eyes: Kayser-Fleischer rings: green to brown deposits of copper in Desçemet's membrane in limbus= pathognomonic
149
• What is the genetic cause of Alpha 1-antitrypsin deficiency?
o AR (chrom 14), >100 mutations
o Normal allele: PiM; mc abn: PiS and PiZ; lysine replaces glutamine →dysfxn
o Hets P PiMS and PiMZ st → pulmonary, liver dz, less often severe
o Homo PiSS and PiZZ (most likely), het PiSZ, more likely → significant COPD, liver dz. The persons most likely to develop severe AAT deficiency and its complications have PiZZ
o 1:10 of Euro descent has 1 of 5 abn phenotypes (normal is PiMM)
150
• What is Alpha 1-antitrypsin? Common eficiency manifestations? Micro liver?
o important protease inhibitor, esp lung elastase, others, which are normally released from Ns in inflam
o → significant liver damage (MC kids); defective enzyme trapped in liver → cirrhosis
o Lund dz, mc adults: emphysema
151
• What is micro appearance of liver w A1AT deficiency?
o round or oval cytoplasmic globular inclusions of defective A1AT in hepatocytes
o periportal red hyaline globules seen w periodic acid-Schiff (PAS) stain
152
• what is Primary biliary cirrhosis (PBC)? Tx?
o slowly progressive form of liver inflammation (infiltration M0s, Ls)
o chronic, progressive, often fatal
o 1:3-4000; F:M 6-9:1; 20-80, peak 40-50
o AI, T cell mediated destruction of liver bile ducts → clogged or destroyed
o → fibrosis, degeneration of hepatocytes → cirrhosis (not all cases)
o Tx: liver transplant, st recurrence
153
• What is histo appearance of PBC?
o granulomatous destruction of medium sized intrahepatic bile ducts
o Sheets of inflammatory cells, portal tracts destruction
154
• What are ssx of PBC?
o Abd pn dt HM
o Fatigue, foul oily stool
o xanthomas, xanthelasmas (esp eyelid) (↑ cholesterol)
o Later: Cirrhosis, jaundice, severe pruritus dt bile salt deposition in skin
o Complications: portal HTN, ascites, hypersplenism, E varices
o End stage: encephalopathy → hepatic coma
o Labs: ↑ALP, GGT, cholesterol
o ** (+) anti-mito Ab (up to 95%)
o Assoc extrahepatic AI: RA, Sjögren's syndrome (up to 80%)
155
• What is Primary sclerosing cholangitis (PSC)? Ddx?
o Slow progression, Intra/extra-hepatic bile ducts initially inflamed → fibrosis, scar
o barium: characteristic beaded appearance of biliary tree (usu endoscopic retrograde cholangiopancreatography, ERCP)
o segmental stricture and dilatation of bile ducts (beading)=dx feature
o ddx: PBC, drug induced cholestasis, cholangiocarcinoma, HIV-assoc cholangiopathy
156
• what labs are done for PSC?
o most have auto-Abs, but not specific
o 80%: perinuclear anti-neutrophil cytoplasmic Abs (p-ANCA), nut not specific
o 20-50%: Antinuclear and anti-smooth muscle Abs
o CBC, electrolytes, renal function, liver enzymes (↑ALP, GGT), ↑bilirubin
o Fecal fat determination if malabsorption sxs (→def fat-sol vits, A,D,E,K)
157
• What is etio of PSC? prevalence?
o Unknown etio, persistent inflammation → scarring blocks ducts →cholestasis, bile lakes → biliary cirrhosis, liver failure
o Theory: toxins from inflamed gut, immune mediated injury, ischemic damage
o M:F 2:1, usu 20-30; ~1/100,000
158
• What is assoc w PSC? Tx?
o Assoc: coexisting IBD (70% have UC, 4-5% of UC have PSC)
o Cholangiocarcinoma (10-15%)
o Colon CA
o Tx: liver transplant (if recurrent bacterial cholangitis, jaundice refractory to med, endoscopic, decompensated cirrhosis, portal HTN)
159
• What is histo appearance of PSC? Ssx? Dx?
o Classic onion skin appearance: concentric, circumferential layering of fibrous tissue surrounding damaged bile ducts
o Mb asx, pruritis, jaundice, fatigue
o Dx: ERCP dx, bx, **(-) a-mito Ab
