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Block 7: Endocrine, GI, Repro > Week 7 (Hepatobiliary) > Flashcards

Week 7 (Hepatobiliary) Flashcards

1
Q

Porta hepatis

A

Hepatic artery: 30% of blood supply; from systemic circulation

Portal vein: 70% of blood supply; from GI tract and spleen

Bile duct: delivers bile from liver to gall bladder and then duodenum; receives arterial blood via a branch of hepatic artery

Also includes nerves and lymphatics

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2
Q

Two concepts of microarchitecture of liver

A

Lobular: organized around the central veins (terminal hepatic veins), with portal tracts at the periphery; (hexagons!)

Acinar: metabolic lobules organized around the blood supply; wedge shaped segments with branches of portal tracts (blood supply) at base and central veins at apex; 3 zones depending upon distance from blood supply; enzymatic gradient within hepatocytes across the acinus; more metabolically accurate/relevant but less obvious from looking; (triangles!)

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3
Q

Microarchitecture of the liver

A

Parenchyma is organized into anastamosing sheets of hepatocytes (1 hepatocyte thick) separated by vascular sinusoids

Sinusoids are lined by endothelial cells

Kupffer cells (macrophages) reside in sinusoids

Microvilli of hepatocytes project into space of Disse which is between the sinusoidal endothelium and hepatocyte

Stellate cells in space of Disse also

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4
Q

Stellate cells (Ito cells)

A

Reside in the space of Disse, hard to see in routine histology!

Mesenchymal cell

Normal conditions: storage of vitamin A (can get large and foamy if lots of vitamin A)

Chronic injury: transform into myofibroblasts, make collagen

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5
Q

Bile flow in the liver

A

Canaliculi formed by grooves in cell membranes of hepatocytes

Bile secreted into canaliculi (ATP dependent)

Bile travels between hepatocytes to portal tracts

Terminal hepatocytes (periportal) form canals of Hering which enter the portal tract to join the interlobular bile ducts

Note: cholestasis can result from ischemic injury to the liver because bile secretion requires ATP

Canaliculi –> interlobular bile ducts (part of portal tracts) –> intrahepatic bile ducts –> R and L hepatic ducts –> common hepatic duct

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6
Q

Portal tracts

A

Normal collagenous zone containing branches of the bile duct, artery and portal vein

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7
Q

Limiting plate

A

Plate of hepatocytes which abuts the portal tract

Interface between portal tract and parenchyma (hepatocytes)

Note: if inflammation past this point, is interface activity

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8
Q

Hepatocellular changes

A

Ballooning degeneration: lysis of cells

Acidophil bodies: apoptosis

Steatosis: fatty accumulation in hepatocytes

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9
Q

Distribution of injury to hepatocytes

A

Random: scattered randomly

Panlobular: entire lobule or acinus

Zonal: limited to certain zones; periportal (zone 1) vs. pericentral (zone 3)

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10
Q

Normal architecture

A

Normal: regular alternation of portal and central structures

Abnormal: regenerative areas of parenchyma without portal or central vessels

Hepatocellular plates: normally one cell thick (widened in regeneration and neoplasia)

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11
Q

Types of hepatitis

A

Acute viral hepatitis

Chronic viral hepatitis

Chronic autoimmune hepatitis (or acute)

Steatohepatitis

Drug induced hepatitis (acute and chronic)

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12
Q

Hepatitis caused by HSV, adenovirus, CMV, rubella, EBV

A

These systemic viruses may cause mild or asymptomatic hepatitis

May cause severe hepatitis even fulminant hepatic failure in newborns or the immunosuppressed

Note: EBV causes increase in liver enzymes

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13
Q

Hepatotrophic viruses

A

Viruses which primarily or exclusively infect and cause damage to the liver

Acute hepatitis: varying severity from mild to massive hepatic necrosis

Chronic hepatitis: stable disease (nonprogressive) or relapsing and remitting disease resulting in cirrhosis

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14
Q

Acute hepatitis

A

Hep A and E

Variable severity from subclinical to fulminant hepatic failure due to massive hepatic necrosis

Histologic features are similar for all types

Drug induced hepatitis may have similar histology

Distinction is based on serologic studies not histology

Mainly lobular inflammation with lymphocytes, fewer neutrophils, eosinophils and plasma cells; few inflammatory cells in portal tracts; Kupffer cell hypertrophy

Hepatocellular regeneration (mitosis, binucleate cells, and focally thickened hepatocellular plates); may have fatty change; canalicular bile

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15
Q

Histology of acute hepatitis

A

Active hepatocellular injury and necrosis

Ballooning: swelling of cells and nuclei leading to lysis; results in small foci of stromal collapse; small clusters of lymphocytes and/or Kupffer cells remain

Acidophilic degeneration (apoptosis): condensation of cytoplasm, shrunken fragmented nuclei; acidophil bodies remain; these small shrunken cells are eventually phagocytized

Massive necrosis and don’t see hepatocytes anymore

Collapsed reticulin as result of necrosis

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16
Q

Resolution of acute hepatitis

A

Lobular inflammation recedes, portal inflammation may remain longer

Damaged and necrotic cells recede

Regenerative activity increases

Clusters of enlarged Kupffer cells remain behind (Kupffer cell hypertrophy indicates previous injury but not current)

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17
Q

Chronic hepatitis

A

Hep B, C, D, E?!

1-10% with acute Hep B develop chronic Hep B

80% with acute Hep C develop chronic Hep C

Hep E can be chronic in immune compromised patients

Chronic autoimmune hepatitis

Persistent often progressive inflammatory process characterized by lymphocytic inflammation in the portal tracts with varying degrees of parenchymal inflammation, hepatocellular injury and fibrosis

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18
Q

What diseases mimic chronic hepatitis?

A

Hemochromatosis: iron storage disease

Wilson’s disease: copper storage disease

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19
Q

How do you tell the difference between resolving acute hepatitis and chronic hepatitis?

A

Slowly resolving acute hepatitis can be histologically similar to chronic hepatitis

Require evidence of liver disease or infection for 6 months or more (then almost all cases of resolving acute hepatitis are eliminated)

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20
Q

Classification of chronic hepatitis

A

1) Etiologic agent: B, C, autoimmune or other; requires serologic studies (histologic features provide clues but are not reliable)
2) Activity (how much inflammatory activity): interface activity (inflammation which extends across limiting plate and is associated with ballooning or necrotic hepatocytes); lobular activity (clusters of lymphocytes in lobules in association with ballooning or necrotic hepatocytes)
3) Stage (how much fibrosis): one of most important reasons to perform liver biopsy; expansion of portal tracts, periportal septa, bridging of portal tracts, relatively little fibrosis within lobules

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21
Q

Hepatitis B

A

Ground glass hepatocytes: massive amounts of surface antigen

Immunoperoxidase stains for surface and core antigens of HBV: positive result confirms presence of virus but does not correlate with inflammatory activity; negative result does not rule out Hep B infection

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22
Q

Pathogenesis of viral hepatitis

A

Hepatotrophic viruses have little or no direct cytopathic effect on hepatocytes

Most studies demonstrate antigen specific antiviral cellular immune response with predominantly lymphocytic infiltrates, and widely variable clinical outcome for identical viruses

Intracellular viral inactivation by cytokines may occur

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23
Q

What does the liver do?

A

Nutrient synthesis, metabolism and interconversion (carbohydrates, lipids, proteins)

Detoxification (endogenous and exogenous substances)

Bile synthesis and recycling (lipid absorption)

Immune surveillance and clearance (endogenous and exogenous)

Removal of substances from the sinusoidal blood

Metabolism and biotransformation of several substances

Intracellular synthesis of new products

Intracellular storage

Secretion of substances into bile and sinusoidal blood

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24
Q

What are the consequences of liver failure?

A

Imapired nutrient handling: hypoglycemia, coagulopathy, atrophy (no protein synthesis so no muscle)

Impaired detoxification: encephalopathy, drug OD, pruritus

Impaired bile synthesis and recycline: fat soluble vitamin and lipid malabsorption

Impaired immune surveillance and clearance: increased risk of infection

Alterations in hepatic circulation: portal hypertension

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25
Q

Predominant manifestations of liver disease

A

Acute hepatocellular injury

Biliary dysfunction

Cirrhosis

Hepatic masses

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26
Q

Liver diseases

A

Toxins: dose-dependent, idiosyncratic

Infectious: viral, bacterial, parasitic, fungal

Neoplastic: malignant, benign, hepatic, metastatic

Metabolic: pediatric, adult onset

Autoimmune: hepatocyte, biliary

Vascular: pre, intra, post-sinusoidal

Biliary: parenchymal, obstructive

Systemic

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27
Q

Neoplasms that metastasize to the liver

A

GI

Reproductive

Breast

Lung

Lymphoma

Melanoma

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28
Q

Hepatocellular tumors

A

Benign: focal nodular hyperplasia, hepatocellular adenoma, macroregenerative nodule

Malignant: hepatocellular carcinoma, fibrolamellar hepatocellular, hepatoblastoma

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29
Q

Biliary epithelial tumors

A

Benign: bile duct adenoma, biliary microhamartoma, biliary papillomatosis, biliary cystadenoma

Malignant: intrahepatic cholangiocarcinoma, biliary cystadenocarcinoma

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30
Q

Metabolic disorders of the liver

A

Non-alcoholic fatty liver disorders (now more tx done for this than for alcoholic liver!)

Pregnancy-related liver diseases

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31
Q

Autoimmune liver/biliary disorders

A

Autoimmune hepatitis (AIH)

Primary biliary cirrhosis (PBC)

Primary sclerosing cholangitis (PSC)

Overlap syndromes

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32
Q

Vascular hepatic disorders

A

Arterial: ischemic necrosis (ischemia to liver usually due to heart problem/hypotension), hepatic infarction

Sinusoidal: peliosis hepatis

Venous: Budd-Chiari syndrome, sinusoidal obstruction syndrome (VOD), congestive hepatopathy (NRH)

Portal: portal vein thrombosis, splenic vein thrombosis

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33
Q

Biliary diseases

A

Obstructive: stones, neoplasm, trauma, cystic fibrosis

Hepatocellular: acute injury, cirrhosis, hereditary

Biliary epithelium: PBC, PSC, ascending cholangitis

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34
Q

Systemic diseases causing liver abnormalities

A

Sarcoidosis

Amyloidosis

Sickle cell anemia

Sepsis

Post-operative cholestasis

Rheumatoid arthritis

Lupus

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35
Q

Acute hepatocellular injury

A

Acute and self-limited condition resulting from acute hepatocyte necrosis or malfunction

Clinical presentation ranges from asymptomatic lab test abnormalities to life-threatening fulminant hepatic failure

Etiology: medications, toxins, viruses, autoimmune, metabolic, vascular

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36
Q

Cirrhosis

A

Irreversible condition of diffuse destruction and regeneration of hepatocytes in which scar tissue (fibrosis??) has resulted in derangement of lobular and vascular architecture

Clinical presentation ranges from asymptomatic histopathologic cirrhosis to decompensated cirrhosis with life-threatening complications

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37
Q

Biliary dysfunction

A

Any of a variety of disorders exhibiting jaundice as the predominant abnormality

Clinical presentation includes asymptomatic (as benign bile transport abnormalities) to acute obstructive jaundice (with colangitis) to chronic irreversible PBC or PSC

Etiologies: obstruction, hepatocellular or biliary injury or malfunction

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38
Q

Hepatic masses

A

Any of a variety of processes which manifest as a discrete hepatic lesion on imaging or histopathological studies

Clinical presentations range from transient pseudotumors caused by focal fat to benign hemangiomas to hepatocellular carcinoma

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39
Q

Etiologies of hepatic masses

A

Hep B, Hep C, HHC, cirrhosis –> HCC

PSC –> cholangiocarcinoma

Estrogens –> hepatic adenomas

Common bacteria, ameba –> abscesses

Rheumatoid arthritis –> non-cirrhotic nodules

Steatosis –> pseudotumors

Polycystic disease, ecchinococcus –> hepatic cysts

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40
Q

Clinical presentation of liver disease

A

Symptoms: jaundice, dark urine, clay colored stool, abdominal pain, itching, GI bleeding, increased abdominal girth, changes in mental status

Physical exam: oral lesions, JVD, ascites, palpable liver or spleen, hepatic bruit, Cruveilhier-Baumgarten murmur, shifting dullness

Lab tests: CBC, liver panel, renal tests, serologies, iron studies, uric acid

Imaging: ultrasound, CT scan, MRI, nuclear medicine scan, PET scan

Biopsy

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41
Q

Patient history to consider in liver disease

A

PMH: diabetes, heart disease, lung disease, neurologic diseases, autoimmune diseases

PSH: CCY, biliary or abdominal surgeries

FH: hemochromatosis, Wilson’s disease, alpha1-antitrypsin deficiency, DM, viral hepatitis

SH: alcohol abuse, IVDA, recreational drugs, tattoos, blood transfusions, acupuncture, recent travel, sexual behavior

Meds: acetaminophen, amiodarone, INH, herbs, alternative meds

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42
Q

Standard liver tests

A

Tests of hepatocyte damage: AST (SGOT) and ALT (SGPT)

Tests of cholestasis: alkaline phosphatase, GGT, bilirubin

Tests of liver synthetic function: prothrombin time, albumin

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43
Q

Tests of hepatocyte damage

A

Cell injury results in aminotransferase leakage

Aspartate aminotransferase (AST): cytosolic and mitochondrial enzyme found in liver, muscle, kidney and pancreas

Alanine aminotransferase (ALT): cytosolic enzyme found in liver

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44
Q

Tests of cholestasis

A

Alkaline phosphatase (AP): reflects increased synthesis and release into serum; found in small bile ducts, bone, placenta and intestine

Gamma-glutamyl transferase (GGT): inducible microsomal enzyme, little found in bone or placenta

Bilirubin: produced as a breakdown product of hemoglobin; conjugated and excreted by the liver

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45
Q

Tests of liver synthetic function

A

Prothrombin time (PT): liver synthesizes major coagulation factors, except 8; PT is dependent on vitamin K dependent factors; coag factors have short half-life (6 hours for factor 7)

Albumin (Alb): synthesized by liver but dependent on nutrition and pathological losses; 3 week half-life

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46
Q

What can cause cholestasis?

A

Hepatocellular injury

Canalicular injury

Microscopic duct injury

Macroscopic duct injury (intrahepatic or extrahepatic)

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47
Q

Sites of intrahepatic cholestasis

A

Bile canaliculus: hepatocellular injury (viral, alcoholic hepatitis), drugs, pregnancy

Bile ductule: drugs (cholangiolitis)

Portal tract bile ductule: primary biliary cirrhosis, intrahepatic biliary atresia

Medium and large interlobular bile ducts: sclerosing cholangitis, cholangiocarcinoma

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48
Q

Canalicular cholestasis

A

Numerous drugs

Acute alcoholic injury

Ischemia

Postoperative

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49
Q

Bile duct disease

A

Obstruction and/or injury of bile ducts of any size may result in cholestasis

Distinction between various types of bile duct injury often requires combination of histologic radiographic and serologic studies

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50
Q

Microscopic duct cholestasis

A

Primary biliary cirrhosis (PBC)/autoimmune cholangitis: immune mediated destruction of small (interlobular) bile ducts

Drugs

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51
Q

Primary biliary cirrhosis

A

Autoimmune disease that results in destruction of small bile ducts (within the liver!)

Mononuclear inflammatory lesions centered on small bile ducts

Granulomas often present (histiocytes surrounded by lymphocytes); interface with surrounding parenchyma is pretty smooth which means is biliary disease

Bile flow interrupted –> upstream portal areas expand/become inflamed

Proliferating ductules/ductal reaction

Portal tract scarring leads to bridging fibrosis and ultimately cirrhosis

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52
Q

Macroscopic duct cholestasis

A

Cholangiocarcinoma (obstructs the duct and prevents bile from getting out)

Caroli’s disease (congenital cystic dilation of large bile ducts)

Primary sclerosing cholangitis (PSC)

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53
Q

Extrahepatic duct cholestasis

A

Primary sclerosing cholangitis (PSC): autoimmune mediated destruction of large (extrahepatic or intra (?) bile ducts), frequent association with UC, severity of 2 diseases is unrelated

Cholangiocarcinoma

Pancreatic carcinoma

Gallstones

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54
Q

Primary sclerosing cholangitis (PSC)

A

A progressive inflammatory disease: fibrosis of LARGE intra and extrahepatic bile ducts

Cholangiogram demonstrates strictures in large duct(s) (beads on a string)–liver biopsy/histology doesn’t always tell you diff between PSC and PBC (need cholangiogram)

Increased risk of cholangiocarcinoma

Histology: nonspecific (cannot be used to distinguish from other causes of large duct obstruction); large portal areas and ducts (early on, concentric periductal edema and mononuclear inflammation; later on concentric fibrosis (onion skin fibrosis) and ultimately fibrous obliteration of bile duct); portal tract scarring leads to bridging fibrosis and ultimately cirrhosis

Elevated p-ANCA

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55
Q

What is bile used for?

A

Elimination of waste products: insufficiently water soluble substances that cannot be excreted in urine (bilirubin, cholesterol, others)

Bile salts/acids augment absorption of dietary fat (reabsorbed in terminal ileum)

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56
Q

Gallstones

A

Causes: alteration in composition of bile, stasis (reduced contractility of gallbladder), infection

Composed of cholesterol, bilirubin, bile salts (Ca2+)

Types of gallstones: cholesterol stones contain <50% crystalline cholesterol; pigment stones contain <50% cholesterol (black vs. brown pigment stones)

Formation of cholesterol stones: supersaturation, hypomotility of gall bladder, nucleation into cholesterol crystals, mucous hypersecretion

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57
Q

Cholesterol supersaturation

A

Cholesterol is solubilized by bile salts and phospholipids (lecithins)

When the concentration of cholesterol exceeds the solubilizing capacity of the bile, supersaturation occurs and crystals form

Hypersecretion of cholesterol is most common condition associated with gall stones

Decreased production of bile salts or phospholipid

Decreased reabsorption of bile salts in terminal ileum

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58
Q

Hypomotility and nucleation and mucous hypersecretion

A

High cholesterol concentration is toxic to the gall bladder:

Decreases wall motility and promotes crystal formation

Causes mucous hypersecretion and enhances agglomeration of cholesterol crystals into stones

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59
Q

Risk factors for cholesterol stones

A

Industrial society 25%

Native Americans of first migration (Pima, Navajo, Hopi) 75%

Increasing age

Obesity

Female gender

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60
Q

Why do women get gallstones more than men?

A

Estrogen increases LDL uptake (increased cholesterol uptake by liver)

Estrogen increases HMG CoA reductase activity (increased cholesterol production)

Progesterone decreases gallbladder contractility

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61
Q

Negative feedback of bile salt production

A

Bile salts reabsorbed in terminal ileum

Normally negative feedback causes decreased bile salt production by the liver

Abnormally increased negative feedback results in decreased concentration of bile salts in bile (supersaturation)

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62
Q

Black pigment stones

A

Increased concentration of unconjugated bilirubin in bile

Black: excess unconjugated bilirubin; derived from increased RBC breakdown (hemolytic anemia, G6PD, hemoglobinopathies, prosthetic heart valves), congenital defects in UDPGT, inflammatory conditions of terminal ileum

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63
Q

Brown pigment stones

A

Increased concentration of unconjugated bilirubin in bile

Brown: bacterial and parasitic infestation of biliary tree (organisms elaborate hydrolases which deconjugate bile)

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64
Q

Cholecystitis and gall stones

A

90% of patients with cholecystitis have gall stones

Only 20-30% of patients with stones develop clinically evident cholecystitis

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65
Q

Acute cholecystitis

A

Calculous: 90% of cholecystitis; stone obstructing cystic duct; can happen in anyone

Acalculous probably ischemic (deprive GB of blood, get disease in GB wall): postoperative (nonbiliary), trauma, burns, multisystem organ failure, sepsis; no stone or structural obstruction; usually happens in hospital, as the result of something else

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66
Q

Chronic cholecystitis

A

Most cases is no prior history of acute cholecystitis

Biliary colic, RUQ pain

Low grade inflammation; fibrotic, thickened wall

Rokitansky-Aschoff sinuses: chronically inflamed mucosa proliferates in the form of outpouchings

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67
Q

What can cause RBC congestion in zone 3 (around central veins)?

A

This happens because blood can’t get out of the liver:

Thrombosis of hepatic artery

Cardiac tamponade

Tumor compressing hepatic vein

Drug injury of central vein endothelium that causes thrombosis

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68
Q

Histology of acute vs. chronic hepatitis

A

Acute hepatitis has inflammation in lobular areas

Chronic hepatitis has inflammation in portal areas

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69
Q

What does it mean if you see inflammatory “activity” in the liver?

A

Means that inflammatory cells have left the portal tract by breaking through/exiting the limiting plate

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70
Q

Metabolic diseases of the liver

A

Steatohepatitis

Alpha1 antitrypsin disease

Hemochromatosis

Wilson disease

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71
Q

Substances whose metabolism can be messed up and lead to disease

A

Porphyrin

Carbohydrate (glycogen storage diseases, hereditary fructose intolerance, galactosemia)

Glycoprotein (mucopolysacharidoses, mucolipidoses)

Bilirubin metabolism

Note: we won’t talk about these diseases though

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72
Q

Different types of steatohepatitis

A

Alcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH)

Note: these cannot be reliably distinguished by histology

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73
Q

Non-alcoholic steatohepatitis (NASH)

A

NASH is linked to metabolic syndrome, a variably defined syndrome characterized by:

Insulin resistance

Type 2 DM

Obesity

Hyperlipidemia

Drugs?

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74
Q

Histology of steatohepatitis

A

Steatosis: reversible accumulation of lipid within cytoplasm of hepatocytes

Inflammation: primarly lobular, less portal than in chronic viral hepatitis; lymphocytes and neutrophils

Ballooning hepatocytes: lysis of cells

Mallory bodies: Mallory’s hyaline/alcoholic hyaline; cytoplasmic inclusions composed of cytokeratins, ubiquitin, others (not as well formed in NASH, but not best way to distinguish)

Pericellular fibrosis: fibrosis around cells (not bridging)

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75
Q

Macro- vs. microvesicular steatosis

A

Macrovesicular steatosis: droplets are generally larger than the nucleus, often pushing it to the side of the cell; common to have macro or mixed macro/microsteatosis

Microvesicular steatosis: cells appear foamy due to much smaller size of vacuoles; rare to have a condition that has only microvesicular steatosis (associated with necrosis and steatohepatitis)

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76
Q

Fibrosis in steatohepatitis

A

Most of the fibrosis (and damage in general) is lobular/pericentral (around central vein, zone 3)

Relatively less portal fibrosis than in chronic viral hepatitis

Central to central bridging

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77
Q

Diagnostic criteria for steatohepatitis

A

Disease activity including amount of fat can wax and wane

Steatosis + some manifestation of progressive injury: steatosis alone is reversible; Mallory bodies, ballooning cells and pericellular/lobular fibrosis are the best indicators of progressive disease

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78
Q

Microvesicular steatosis

A

Conditions that cause pure microvesicular steatosis are rare and indicative of severe mitochondrial dysfunction

Frequently associated with necrosis and therefore steatohepatitis

Results from impairment of mitochondrial beta oxidation which causes buildup in fatty acids

Syndromes with primarily microvesicular steatosis: Reye’s syndrome, fatty liver of pregnancy, foamy degeneration/a particularly aggressive variant of alcoholic liver disease, drugs (valproic acid toxicity, IV tetracycline), mitochondrial cytopathies

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79
Q

Alpha1 antitrypsin disease

A

Alpha 1 antitrypsin is a protease inhibitor

Enzyme deficiency (in lungs) and a storage disease (in liver)

Variable clinical presentation (neonatal cholestasis, “cryptogenic cirrhosis” as an adult)

Histology: eosinophilic cytoplasmic globules in hepatocytes

Genetics: more than 75 alleles identified; M is normal/most common allele; Z is allele in disease (lysine to glutamine sub at 342)

ZZ have 15% enzyme activity compared to normal, resulting in an enzyme deficiency

Abnormal alpha 1 antitrypsin protein cannot be properly processed by cells and accumulates in hepatocytes resulting in a storage disease

Null alleles: no protein made, results in enzyme deficiency but no storage disease

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80
Q

Manifestations of alpha1 antitrypsin disease

A

Lung: ZZ phenotype has pulmonary emphysema because decreased enzyme activity allows an elastase made by neutrophils to go “unchecked” causing tissue damage resulting in emphysema

Liver: only a minority of ZZ adults have clinically evident liver disease (cholestasis; prob have biochemical evidence of liver disease though), but abnormal protein accumulates in ER and can be seen on tissue sections as eosinophilic globules in cytoplasm of hepatocytes; only 10% develop cirrhosis

Note: “second hit” hypothesized to be necessary for clinical liver disease

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81
Q

Clinical presentation of alpha1 antitrypsin disease in pediatrics

A

Neonatal (giant cell) hepatitis

Cholestasis due to biliary disease (w/jaundice)

Hepatomegaly

Acholic (pale) stools

Most spontaneously regress within 6 months

Small percent go on to liver failure

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82
Q

Clinical presentation of alpha1 antitrypsin disease in adults

A

Present with clinical features of chronic liver disease

Most have no history of neonatal or pediatric disease

Most are in liver failure within 2 years of presentation

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83
Q

Histology of alpha1 antitrypsin disease in adults

A

Cytoplasmic globules: accumulation of abnormal protein

Chronic hepatitis with interface and lobular activity, periportal fibrosis of varying severity (can mimic viral hepatitis)

Cirrhosis frequently seen at presentation

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84
Q

Hemochromatosis

A

Pathologic accumulation of iron in parenchymal cells of the liver and other organs: hereditary (primary) or secondary (underlying condition causes excess iron–hemosiderosis)

Parenchymal (hepatocellular) hemosiderin is derived via receptor mediated uptake from circulating transferrin and ferritin

More in males, 40-50s

Or females in 50-60s via loss of iron thru menstruation

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85
Q

Primary storage form of iron in hepatocytes

A

Ferritin

Not visible unless present in large quantities

86
Q

Hemosiderin

A

Insoluble, end stage product of ferritin degradation

Refractile yellow granular inclusions in cytoplasm

Increases as amount of iron increases

87
Q

Two basic patterns of iron accumulation

A

1) Parenchymal: hepatocytes
2) Reticuloendothelial: Kupffer cells

88
Q

Iron accumulation in two different places

A

1) Parenchymal (hepatocellular) hemosiderin is derived primarily via receptor mediated uptake from circulating transferrin and ferritin (this is mode of uptake in genetic hemochromatosis)
2) Reticuloendothelial (Kupffer cell) hemosiderin is derived primarily from senescent RBCs (get iron buildup in Kupffer cells in: secondary hemochromatosis, repeated blood transfusions, hemolysis, Bantu siderosis)

89
Q

Distinction between hepatocellular and Kupffer cell iron in disease

A

Early in disease, easy to tell if iron is in hepatocytes or in Kupffer cells

As hemosiderin accumulates it causes hepatocellular damage and necrosis –> then hemosiderin is released from hepatocytes and taken up by Kupffer cells

In later stages of diesase, as hemosiderin accumulates in Kupffer cells, it becomes harder to tell whether disease is primary (hemosiderin in hepatocytes) or secondary (hemosiderin in Kupffer cells)

90
Q

Histology of genetic hemochromatosis

A

Gradually increasing hepatocellular iron in architecturally normal liver

No inflammation

WIth increasing amounts of iron, get chronic hepatitis with interface activity and lobular activity, fibrosis and cirrhosis

91
Q

Pathogenesis of hemochromatosis

A

Excess iron damages hepatocytes by:

Production of free radicals which cause membrane phospholipid peroxidation

Direct stimulation of collagen production

Interactions with DNA (increased risk for HCC above that for just cirrhosis)

92
Q

Genetics of genetic hemochromatosis

A

Autosomal recessive

HFE gene on chromosome 6: mutation in HFE results in increased absorption of iron from GI tract

Prevalence of HFE mutation is 6% in northern Europeans (0.45% homo; 9% hetero)

Not all homozygotes have excess iron

There are cases of genetic hemochromatosis with no mutation of HFE (other genes involved, esp in non-northern Europeans)

93
Q

Organs involved in hemochromatosis

A

Liver: most commonly involved organ

Heart: secondary cardiomyopathy

Pancreas: diabetes

Skin: bronze (bronze diabetes)

Involvement of these organs is rare in secondary HFE

94
Q

Wilson’s Disease

A

Autosomal recessive disorder

Mutation in copper transporting ATPase

Accumulation of toxic levels of copper (in liver, brain, eye)

Excess copper is eliminated from the body by excretion into bile (this pathway is disturbed in Wilson disease)

Defective biliary excretion of copper leads to buildup and excess copper catalyzes production of free oxygen radicals

Clinical presentation: fulminant hepatic failure, chronic injury mimicking chronic viral hepatitis (cirrhosis), toxic injury to CNS (basal ganglia), deposits in cornea (Kayser-Fleischer rings); decreased ceruloplasmin

Gene ATP7B on chromosome 13 is a transmembrane copper binding ATPase on the canalicular membrane

More than 30 mutations identified and most patients with Wilson’s are compound heterozygotes (2 diff mutations)

Treatment: give metalloproteinases (same tx for hemochromatosis)

95
Q

Histology of Wilson’s disease

A

Early on, have fatty change

Midcourse, have chronic hepatitis (resembles viral) often with fatty change

Later, have cirrhosis

Massive hepatic necrosis resulting in acute liver failure can occur at any stage

96
Q

Clinical diagnosis of Wilson’s disease

A

Chronic hepatitis: low serum ceruloplasmin, increased urine copper, low uric acid (renal tubular acidosis)

Fulminant failure: low alkaline phosphatase, hemolysis, renal failure, low uric acid

97
Q

What happens upstream if you have a large duct obstruction?

A

If you have a large duct obstruction, you will have periductal edema and fibrosis (onion skin fibrosis?) around the small ducts that are upstream

98
Q

Causes of bile duct obstruction

A

Bile duct carcinoma

Enlarged lymph node

Sclerosing cholangitis

Postop stricture

Congenital biliary atresia

Pancreatic carcinoma

Gallstone

Carcinoma of Ampulla of Vater

99
Q

Strwaberry gall bladder

A

Result of cholesterolosis

Villi become packed with foamy macrophages that have lots of cholesterol, and macroscopically see them

Gallbladder has flecks (villi) on it and looks like a strawberry

100
Q

Pancreatic enzymes

A

Proteases 90%

Amylase 7%

Lipases 2%

Nucleases <1%

101
Q

Acute pancreatitis

A

Pathogenesis: interstitial liberation and activation of its own enzymes, occurs in spite of intrinsic protective mechanisms (probably somehow due to local inflammation/cytokines)

Etiology: alcohol, biliary, idiopathic, other (autoimmune, drug-induced, iatrogenic (ERCP always causes amylase to go up but usually doesn’t cause acute pancreatitis), IBD-related, infectious, inherited, metabolic, neoplastic, structural, toxic, traumatic, vascular)

Symptoms: abdominal pain, increased pancreatic enzymes in serum

Histology: inflammation, edema, fat necrosis, hemorrhage

102
Q

Intrinsic protective mechanisms of the pancreas

A

Proenzymes within the cell

Isolated compartments (granules) with inhibitors

Secreted as proenzymes

Activated only in gut lumen

103
Q

Mechanism of acute pancreatitis

A

Insult –> zymogen activation, generation of inflammatory mediators, ischemia –> inflammation and ischemia –>

1) Necrosis, apoptosis
2) Systemic inflammatory response, multi-organ failure

Note: also neurogenic stimulation causes inflammation and ischemia

104
Q

Acute effects of alcohol

A

Sphincter of Oddi spasm

Stimulation of CCK and secretin release

Abnormal blood flow and secretion

Toxic metabolites (non-oxidative, oxidative)

Sensitization to CCK (zymogen activation, cytokine generation)

105
Q

Gallstone pancreatitis mechanisms

A

Not totally understood

Common channel theory: gallstone passing through common bile duct into duodenum and could obstruct and cause bile reflux which could injure pancreas?

Pancreatic duct obstruction: unlikely cause because if you ligate bile duct, get atrophy, not pancreatitis!

106
Q

Hypertriglyceridemia

A

TGs lysed into FFAs which are toxic to the pancreas

Rare cause of acute pancreatitis but may cause chronic pancreatitis also (rare for something to cause both!)

Serum triglycerides usually >1000 mg/dL

Can be drug-induced (alcohol, estrogens, isotretinoin, HIV-protease inhibitors)

107
Q

Diagnostic tests for acute pancreatitis

A

Serum enzymes (lipase and amylase): if >3x normal, then good indication of acute pancreatitis

Ultrasound: best to see gallstones

CT: detects edema, calcifications, fluid collections

CT with IV contrast: detects necrosis

108
Q

Conditions associated with hyperamylasemia and hyperlipasemia

A

Amylase only: paroditis, tumors, ectopic pregnancy, macroamylasemia

Amylase and slightly with lipase: biliary disease, renal failure

Amylase and lipase: pancreatitis, intestinal obstruction, ulceration, ischemia, perforated viscus

109
Q

Natural history of acute pancreatitis

A

Mostly mild

Some severe

Few get organ failure or infection –> death

110
Q

Prognosis of acute pancreatitis

A

Bedside assessment underestimates severe disease

Scoring systems: Ranson, Glasgow, Apache, Rabanek

Serum markers: trypsinogen activating peptide (TAP), C-reactive protein (CRP), cytokines

CT criteria: fluid collections, necrosis

Early indicators of severity: tachycardia, hypotension, tachypnea, hypoxemia, hemoconcentration, oliguria, mental status changes (encephalopathy)

Gray-Turner sign: bruising in flank due to retroperitoneal bleeding

111
Q

Ranson’s Severity Criteria

A

Admission: age >55, WBC >16K/mm3, Glu >200, LDH >350, AST >120

After 48 hours: Hct decrease >10%, BUN increase >5, Ca2+ <8, PaO2 <60, base deficit >4, negative fluid balance >6L

112
Q

Treatment for acute pancreatitis

A

Supportive care: aggressive fluid and electrolyte replacement, monitoring (vital signs, urine output, oxygen saturation, pain), analgesics, antiemetics

Other treatments: acid suppression, antibiotics, NG tube, nutritional support, urgent ERCP

113
Q

Complications of pancreatitis

A

Local: fluid collections (common, usually resolve spontaneously but drain if infected or symptomatic), necrosis, infection, ascites, erosion into structures, GI obstruction, hemorrhage

Systemic: pulmonary, renal CNS, multiorgan failure

Metabolic: hypocalcemia, hyperglycemia

114
Q

Treatment for pancreatic necrosis

A

If sterile: medical therapy, debridement for persistent organ failure

If infected: antibiotics, debridement

115
Q

Pancreatic pseudocysts

A

Localized mature fluid collections

>4 weeks after disease onset

Ductal disruption or previous necrosis

Not lined by epithelium (by definition)

Complications: pain, GI obstruction, infection, erosion, bleeding, rupture

Treatment: endocsopically drain into the stomach (external drainage not successful)

116
Q

Infectious complications of acute pancreatitis

A

Infected necrosis: 1-3 weeks; sepsis, multiorgan failure

Abscess or infected pseudocyst: >4 weeks; fever, abdominal pain, bacteremia

117
Q

Pancreatic cystic neoplasms

A

Serous cystic tumor

Mucinous cystic neoplasm

Intraductal papillary mucinous neoplasm (IPMN): associated with pancreatitis

Solid pseudopapillary neoplasm

Note: pseudocyst is always in your differential for these conditions

118
Q

Chronic pancreatitis

A

Pain, calcification, pancreatic insufficiency, malabsorption, DM

Histology: calcifications, fibrosis, inflammation

Causes: alcoholic, idiopathic, cystic fibrosis, hereditary pancreatitis, hypertriglyceridemia, autoimmne, fibrocalcific (note: biliary tract disease does NOT progress to chronic pancreatitis)

Pathological mechanism: intraductal plugging and obstruction, direct toxins and toxic metabolites, oxidative stress (ROS), necrosis/fibrosis (gets worse as you cycle through phases of acute pancreatitis)

119
Q

Clinical diagnosis of chronic pancreatitis

A

Pain: intermittent or constant, moderate to severe, epigastric with radiation to the back

Steatorrhea: visible oil droplets or grease in stool (increased volume, light color, foul odor)

120
Q

Nutritional management of exocrine insufficiency

A

Diet and exogenous enzymes: modify fat intake, medium chain TGs, enzyme replacement

Vitamins, supplements: fat soluble vitamins, Ca2+, cyanocobalamin (B12)

121
Q

Pain management in chronic pancreatitis

A

No alcohol (low/moderate effectiveness)

Analgesia (moderate)

Enzyme replacement (low)

Neurolytic therapy (moderate short-term)

Pseudocyst drainage (high)

Duct decompression (moderate)

Stone removal (controversial)

122
Q

Surgery for pain relief

A

Control pain

Exocrine insufficiency

Endocrine insufficiency

Quality of life

123
Q

Chronic pancreatitis and pancreatic cancer

A

3-15 fold increase in cancer risk with chronic pancreatitis

Symptoms suggesting cancer: changing pain pattern, weight loss unresponsive to enzyme replacements, development of biliary and/or gastric outlet obstruction, new onset of depression, migratory thrombosis (Trousseau’s syndrome)

124
Q

Hep A

A

RNA virus (picorna)

Fecal-oral

Ig is protective globulin

Vaccine against all HAV strains (HAVRIX, VAQTA)

Can give immune globulin pre-exposure or 14 days post-exposure for treatment

Diagnose by seeing anti-HAV IgM and past infection/lifelong immunity if see anti-HAV IgG

Get HAV viremia after infection, then HAV in stool

Don’t do nucleic acid test for Hep A because it is self-limiting!

125
Q

Hep B

A

DNA virus

Transmitted via blood/body fluids, percutaneous/permucosal

HBIG

Vaccine

126
Q

Hep C

A

RNA virus (flavivirus)

Transmitted via blood/body fluids, percutaneous/permucosal (mostly transmitted from IVDU)

No protective globulin, no vaccine

127
Q

Concentration of Hep B virus in various body fluids

A

High: blood, serum, wound, exudates

Moderate: semen, vaginal fluid, saliva

Low: urine, feces, sweat, tears, breast milk

128
Q

5 phases of chronic Hep B

A

Immune tolerant: if baby gets infected by mother is immune tolerant for first 2 decades; high HBV DNA but low ALT because minimal inflammation

Immune activation: immune system “wakes up” and recognizes Hep B virus and attacks hepatocytes so ALT increases and have active inflammation

Low replicative: have anti-HBe+ and low inflammation, so still HBsAg+ obvi, but just less inflammation so low ALT

Reactivation: lymphocytes become active again, kill hepatocytes and increase ALT because active inflammation

Remission: in some lucky people, HBsAg disappears and is inactive so call these patients in remission

129
Q

What happens if you get Hep B as a child vs. adult

A

Child: 95% become immune tolerant but then develop chronic Hep B

Adult: 95% recover from infection; 5% develop chronic Hep B; note that adults don’t go through immune tolerant phase (didn’t get it as a baby)

130
Q

Immunoprophylaxis against Hep B

A

Hep B immune globulin (HBIG): infants born to HBsAg+ mothers (within 12 hours of birth), sexual exposure (within 2 weeks of exposure), needlestick or mucous membrane exposure, travel to areas of high endemicity for HBV, post liver transplant in someone with Hep B who has damaged liver from acute liver failure or HCC (give HBIG before and after liver out, then after new liver in, then weekly and monthly to prevent new liver from getting Hep B infection)

Hep B vaccines: recombivax HB, Engerix B, Twinrix (HAV and HBV): infants born to HBsAg+ mothers, Family members of HBsAg+ patients, universal vaccination for kids, health care workers, MSM/IV drug users, travel to endemic areas

131
Q

Goals/treatment endpoints for chronic HBV

A

Long-term goals of therapy: prevent clinical outcomes such as death from liver disease and development of HCC

Treatment endpoints: normalize ALT, suppress HBV DNA, HbeAg loss and seroconversion to anti-HBe, improve liver histology

132
Q

Current therapies for chronic HBV

A

Immunomodulators: interferon alpha2b (intron A), Peg IFN alpha2a (Pegasys)

Chain terminator: lamivudine (Epivir HBV), adefovir dipivoxil (Hepsera), entecavir (Baraclude), telbivudine (Tyzeka), tenofovir (Viread)

133
Q

Most common cause of chronic hepatitis, cirrhosis and HCC

A

Hep C!

Note: over 1/3 of patients waiting for liver transplants are infected with HCV

134
Q

Natural history of Hep C

A

15-25% recover from acute Hep C infection (anti-HCV+, HCV RNA-)

75-85% develop chronic Hep C (anti-HCV+, HCV RNA+, remember that there is NO HCV IgM test to test for infection) –> after 20-30 years, develop cirrhosis or HCC

135
Q

Anti-viral treatment for Hep C

A

Direct acting antiviral agents (DAA): protease inhibitors (telaprevir, boceprevir)

Recombinant interferon: pegylated interferon (alpha2a, alpha2b)

Ribavirin: oral nucleoside analog

Current treatment: DAAs + pegylated interferon + ribavirin (highest percentage of patients being SVR)

136
Q

Goals of therapy for Hep C

A

Eliminate HCV RNA

Normalize serum AST and ALT

Decrease inflammation and stop/slow progression of fibrosis

Improve clinical symptoms

Stop/slow progression to HCC

137
Q

Responses to antiviral treatment in HCV

A

Null responder: less than 2-log reduction in HCV RNA

Partial responder: greater than 2-log reduction in HCV RNA but doesn’t get down to undetectable levels, and once take off treatment, HCV RNA increases again

Relapser: HCV RNA undetectable at end of treatment but goes up again once taken off treatment

Sustained virologic response (SVR): HCV RNA undetectable 6 months after stopping treatment

138
Q

Interferons as therapy for Hep C

A

Mechanism of action: anti-viral (interferes with RNA and protein synthesis), immunomodulatory (increases ability of immune system (WBCs) to recognize and clear virus), anti-proliferative (BM suppression)

IFNs produced by recombinant DNA technology

139
Q

Ribavirin

A

Synthetic nucleoside analogue

Ribavirin alone is ineffective for treating HCV

Effective when combined with interferon

140
Q

Protease inhibitors for Hep C treatment

A

Protease inhibitor drugs we use target NS3

NS3 is the main viral serine protease: cuts the Hep C polyprotein to release proteins involved in viral synthesis

Inhibiting NS3 prevents cleavage of polyprotein so now proteins needed for viral replication and synthesis not available!

141
Q

What do you do for a baby born to a mother with Hep B?

A

Give HBIG and Hep B vaccine within 12 hours of birth

If you do this, will prevent Hep B infection 90% of the time!

If mother has very high viral load (more than 10^8, more likely that baby will “break through” HBIG and get Hep B–that 10% that do get Hep B infection)

Note: even if mother is HBeAg+ (highly infective), HBIG will help prevent Hep B infection!

142
Q

Anti-HCV

A

This antibody is an antibody to hep C virus, but is NOT protective against virus!

Is made against a recombinant antigen to Hep C but we don’t know what it is

This is why we don’t have Ig for Hep C

143
Q

Genotypes of Hep C

A

7 different genotypes of Hep C

In the USA, genotype 1 is most prevalent, but is different in different countries

Knowing genotype is helpful for predicting duration of treatment and response to anti-viral therapy

144
Q

Cholestasis

A

Failure of normal amounts of bile to reach the duodenum

Liver produces bile but gall bladder stores/pushes it out into duodenum

Cholestasis if hepatocytes have already created bile and put it out into canaliculi, but then there’s a problem!

May cause jaundice (but not all jaundice is cholestatic of course!)

145
Q

Normal bilirubin metabolism

A

1) Spleen breaks down RBCs/heme to produce biliverdin then unconjugated bilirubin
2) Unconjugated bilirubin binds albumin in the blood and goes to liver
3) Liver uses UGT to conjugate bilirubin
4) Liver secretes conjugated bilirubin through bile duct into duodenum
5) In the intestine, bacteria create urobilogen to be excreted in urine and stercobilin to be excreted in feces

Note: need conjugated bilirubin to get into gut in order to make stercobilin to color the feces, but DON’T need it to get into gut in order to get color of urine (conjugated bilirubin itself can leak into blood from damaged hepatocytes and cause dark colored urine!!!)

146
Q

BIlirubin elevated depending on where problem is

A

If pre-hepatic problem, increased unconjugated bilirubin (hemolysis)

If hepatic problem, increased conjugated (and unconjugated) bilirubin

If cholestatic problem (bile unable to reach duodenum for any reason), increased conjugated (and unconjugated) bilirubin

147
Q

Pre-hepatic jaundice

A

Increased UB

Hemolysis (intra or extravascular)

Decreased bilirubin uptake (shunts, CHF, Gilbert’s syndrome)

Decreased bilirubin conjugation (Crigler-Najjar I & II)

Less apparent, no itching, normal color urine (because conjugated bilirubin is NOT leaking into the blood to color the urine dark)

Increased unconjugated bilirubin, increased LDH, reticulocytes, normal AST and ALT, decreased haptoglobin

Fragmented RBCs

148
Q

Hepatic jaundice

A

Increased CB and UB

Decreased excretion (Dubin-Johnson, rotor)

Hepatocellular injury (hepatitis, cirrhosis, Wilson’s, drugs, sepsis (bacteria secrete toxins that block excretion of bile into canaliculi), postop jaundice)

Apparent jaundice, dark urine (because conjugated bilirubin leaking out of hepatocytes, into blood and intoo urine), signs and symptoms of liver disease

Increased ALT and AST

149
Q

Cholestatic jaundice

A

Increased CB and UB?

Anything that can cause cholestasis: PBC, PSC, common bile duct stone, neoplasia, strictures, HIV, PFIC I/II/III, parasites, systemic, medications, TPN

Pruritus, steatorrhea (decreased bile to absorb fat!)

Increased bili, alk phos, AST, ALT, cholesterol, bile acids

Vitamin K, A, D, E malabsorption

150
Q

Intrahepatic vs. extrahepatic cholestasis

A

Intrahepatic: alteration of patterns of secretion of bile by hepatocytes; obstruction of intrahepatic bile ducts

Extrahepatic: obstruction of extrahepatic bile ducts

151
Q

Hepatocellular cholestasis

A

Genetic: alpha 1 antitrypsin deficiency, benign recurrent intrahepatic cholestasis, Byler syndrome, cholestasis of pregnancy, abnormal bile acid synthesis, porphyrias

Acquired: medications, cholestatic hepatitis, bacterial infections, TPN, paraneoplastic cholestasis, postop cholestasis, misc

152
Q

Obstruction of intrahepatic bile ducts

A

Primary biliary cirrhosis (PBC)

Space occupying lesions: primary or metastatic liver cancer, lymphoma, amyloidosis

Vanishing bile duct syndrome: allograft rejection, GVHD, Alagille’s syndrome, idiopathic adult ductopenia, PSC, Hodgkin’s disease, augmentin

Cystic fibrosis

153
Q

Obstruction of extrahepatic bile ducts

A

Common bile duct stone

Pancreatic cancer

Ampullary cancer

Cholangiocarcinoma (cancer of the bile duct)

Benign strictures

Parasites

PSC

HIV cholangiopathy

Lymphoma

Choledocal cyst

BIliary atresia

154
Q

Pruritus

A

Generalized, constant or intermittent, exacerbated at night or during warm weather

Distressing, and has lead to suicide

Pathogenesis controversial

Bile acids theory: increased bile acids in skin and blood, bile acid-binding resin/sequestrant (cholestyramine) is effective; however probably not correct because no correlation between bile acids in skin and itching

Opioid receptors theory: opiates induce facial scratching in animals, endogenous opioids accumulate in cholestasis, plasma extracts induce facial scratching in monkeys, opioid antagonists relieve pruritus

Common symptom with cholestasis?

155
Q

Steatorrhea

A

Decreased bile acid concentration in intestine –> impaired micelle formation –> inadequate fat solubilization –> malabsorption of dietary fats

156
Q

Vitamin deficiencies

A

Malabsorption of dietary fats –> fat soluble vitamin malabsorption

Vitamin A: night blindness

Vitamin D: bone disease

Vitamin E: cerebellar ataxia, peripheral neuropathy, retinal degeneration (in kids)

Vitamin K: coagulopathy

157
Q

Xantomas

A

Due to hypercholesterolemia

Resolve after relieving the obstruction

158
Q

Hepatic osteodystrophy

A

Osteopenia and osteoporosis

Multifactorial: vitamin D (but NOT due to deficiency in vitamin D or Ca2+), calcitonin, hormonal factors, immobility, reduced muscle mass

Prevalence: 30-50%

Fractures: 7-10%

Improves after OLT

159
Q

Biliary cirrhosis

A

From longstanding obstruction (can be only a few months)

Complications of portal HTN are very common

Hepatocellular carcinoma is rare

160
Q

Lab tests for cholestasis

A

Hyperbilirubinemia

Increased alkaline phosphatase

Increased 5’ nucleotidase (specific for liver, so if this is elevated, tells you alk phos IS because of liver!)

Increased ALT and AST

Increased bile acids

Increased cholesterol

Increased copper

161
Q

Management of pruritus

A

Drugs: cholestyramine (sequesters bile acids), ursodiol (makes bile soluble to be secreted into canaliculi), antihistamines (just put pt to sleep!), rifampin, phenobarbital, opioids

If drugs don’t work/severe cases: plasmapheresis/hemoperfusion is transiently effective

Phototherapy is beneficial in anecdotal reports

OLT is indicated when pruritis associated with chronic liver disease, is refractory and is impacting quality of life

162
Q

Management of fat and vitamin malabsorption

A

Adequate caloric intake

30-40g fat per day

Medium chain TGs

Ca2+ supplements

Parenteral vitamin K (no bile so no absorption of vitamin K in gut)

Document and replace vitamins A, D, E

163
Q

Management of bone disease

A

Bone densitometry

Correct vitamin D deficiency

Ca2+ supplements

Biphosphonates (alendronate)

Calcitonin and fluoride (experimental)

HRT

Prevention through physical exercise, avoid steroids

164
Q

Management of extrahepatic biliary obstruction

A

Relieve the obstruction (ERCP, PTC, surgery)

Treat the underlying condition

165
Q

Increased bilirubin and increased LFTs DDx

A

If greater increase in ALT and AST: do viral serologies, ANA, SMA, tox screen, ceruloplasmin –> then maybe liver biopsy to look for cause of hepatitis, inflammation

If greater increase in alk phos: if no biliary duct dilation, do liver biopsy to look for intrahepatic cholestasis; if dilated ducts (on ultrasound), do CT/ERCP to look for obstruction

166
Q

Relationship of NAFLD and NASH

A

NASH is a subset of NAFLD

Prevalence of NAFLD around 24%; prevalence of NASH is 6.3%

NAFLD is a spectrum: fat (which can cause benign fatty liver) –> fat with inflammation (which can turn into NASH) –> cirrhosis (which can turn into HCC)

167
Q

What determines whether fat with inflammation will turn into NASH?

A

Inflammatory response against neoantigens placed in lipid-laden hepatocytes

168
Q

Non-alcoholic fatty liver disease (NAFLD)

A

NAFLD is most common liver disorder in world and most common etiology of increased LFT in the US

Diagnosis: fatty infiltration of the liver, non-alcoholic

Steatosis in 70% of obese people and even 35% of lean people

Presents in 30-50s

Familial clustering (no genetic marker though)

In hispanics and blacks, M:F same but in whites, males affected more than females

169
Q

What is important in determining who will have NASH?

A

Waist to hip ratio (>0.9) but NOT BMI

170
Q

Conditions associated with NAFLD

A

Metabolic: obesity, diabetes (glucose intolerance, insulin resistance, hyperinsulinemia), hyperlipidemia (cholesterol or TGs), rapid weight loss, TPN, acute starvation

Inborn errors of metabolism: Wilson’s disease, abetalipoproteinemia, tyrosinemia, hypobetalipoproteinemia

Surgical procedures: jejuno-ileal bypass, biliopancreatic diversion, extensive small bowel resection, gastroplasty for morbid obesity

Drugs/toxins: amiodarone, glucocorticoids, perhexiline maleate, synthetic estrogens, tamoxifen, diltazon, DHEAH, HAART, isoniazid, industrial exposure to petrochemicals

Misc: partial lipodystrophy, jejunal diverticulosis with bacterial overgrowth

171
Q

Metabolic syndrome

A

Insulin resistance DM

Hyperlipidemia

Hypertension

Truncal obesity

NAFLD

172
Q

Biochemical abnormalities of insulin resistance

A

Obesity, genetics, environment, diet and activity –> increased lipolysis –> increased FFA –> decreased metabolic clearance of glucose by the muscle and increased hepatic glucose output –> increased glucose load –> hyperinsulinemia –> pancreas works really hard until it quits and you develop diabetes

173
Q

Two hit hypothesis of developing NASH from NAFLD

A

Uncoupled oxidation and phosphorylation

1) Increased ROS
2) Decreased antioxidants

Increased oxidative stress within the hepatocytes causes progression from NAFLD to NASH

174
Q

Common and uncommon features of NAFLD

A

Common: asymptomatic (48-100%), hepatomegaly, 2-4 fold elevation of ALT and AST, AST/ALT<1 in most cases, alk phos elevated in 1/3, elevated serum ferritin (53-62%)

Uncommon: vague RUQ pain, fatigue, malaise, splenomegaly, spider angiomata, palmar erythema, ascited, low titer ANA, elevated transferrin saturation, Cys282Tyr mutation of HFE

175
Q

Natural history of NAFLD

A

Most (59%) remain stable

13% improve

28% progress to cirrhosis

This is not fully understood though

176
Q

Treatment of NAFLD

A

Note: all studies bad, no good evidence for these treatments

Weight reduction (probs no benefit!)

Lipid lowering agents (clofibrate, atorvastatin, gemfibrozil) or urodeoxycholic acid but no evidence to use these medications because studies bad quality

Vitamin E

Antioxidants

Metformin

Orlistat

Rimonabant: endocannabinoid type 1 receptor blocker

Thiazolidinedions (-glitazones): have side effects, so don’t want to use in someone who just has fatty liver (vitamin E better too!)

Coffee!!

177
Q

Weight loss surgeries

A

Restrictive: vertical gastroplasty, lap band, roux en Y gastric bypass

Malabsorptive: jejunal ileal bypass, gastric diversion (these more likely to cause liver diseases)

In general, getting WLS decreases death from MI, cancer, diabetes, heart disease

178
Q

Laparoscopic adjustable gastric banding (lap band)

A

Weight loss

Histologic improvement (91%)

Improvement of liver tests

Improvement in metabolic syndrome

179
Q

Roux-en-Y gastric bypass

A

Decreased BMI

Decreased metabolic syndrome

Decreased LFTs

Histologic improvement (89%)

180
Q

Gastric sleeve pre-OLT

A

Surgery to do before patient gets liver transplant to control metabolic syndrome, DM, HTN to have less complications and shorter hospital stay

181
Q

Why is fatty liver bad for the patient?

A

Worse response to ischemic injury (less ATP, less ability to regenerate, necrosis instead of apoptosis for cell death)

Also if graft/tx fatty liver into a patient, they will have lower survival and Hep C will recur more often

182
Q

What should we tell patients with fatty liver?

A

Exercise

Control weight

Eat well-balanced diet

Control your DM and HTN

Avoid alcohol

Decrease fructose intake (high calorie)

Vitamin E (controversial)

Early steroid taper

Bariatric surgery (BMI>40 with failed diet and exercise)

183
Q

Why do some people with liver disease get cirrhosis and others don’t?

A

Probably a genetic defect in liver repair mechanism

184
Q

What things usually cause cirrhosis

A

Chronic injury over years (not trauma or single acute insult like acetaminophen OD):

Hep C

Alcohol

Obesity

Insults may be synergistic

Usually more than 1 things causing cirrhosis

Also: NASH, Hep B, autoimmune, chemicals, drugs, Wilson’s, hemochromatosis, alpha1-antitrypsin deficiency

185
Q

2 stages of cirrhosis

A

Compensated: maybe unaware that they have cirrhosis, asymptomatic

Decompensated: ascites, hepatic encephalopathy, variceal bleeding

186
Q

10 year cumulative probability of complications of cirrhosis

A

Ascites 47%

Encephalopathy 28%

Gut bleeding 25%

187
Q

How do you diagnose cirrhosis?

A

Liver biopsy is gold standard

Transjugular biopsy possible

Clinical diagnosis may be okay, and is common (history, physical, labs, imaging)

188
Q

Signs and symptoms of alcoholic cirrhosis

A

Silent (seen at autopsy or in OR)

Fatigue

Weight loss

Stigmata: vascular spider angioma (blanches; not seen below umbilicus), palmar erythema, abdominal wall collaterals

PE: palpable liver and/or spleen, ascites, asterixis

Labs: low platelets (<160,000), high INR, abnormal AST, ALT, bilirubin, low albumin, low BUN

189
Q

Why do you have thrombocytopenia in cirrhosis?

A

Low platelets (thrombocytopenia) in cirrhosis can be mistaken for immune thrombocytopenia (ITP)

Hypersplenism (esp in Hep C)

Low thrombopoeitin

Anti-platelet antibodies

Sequestration of platelets in liver and spleen

190
Q

Diet in cirrhosis

A

No prophylactic protein or Na+ restriction

Achieve BMI 20-25

No alcohol (0% of active drinkers alive after 3 years)

Avoid excess vitamin A

Aboid herbals except vitamin D, which you should supplement! Target vitamin D >30

191
Q

Medications in cirrhosis

A

Acetaminophen (Tylenol) is actually fine (<4000mg/d is ok!)

Tramadol okay if acetaminophen isn’t strong enough

NO NSAIDs!

Trazodone or hydroxyzine for insomnia (not benzos bc cause coma)

Minimize narcotics

192
Q

MELD Classification

A

Model for End Stage Liver Disease (MELD):

INR, total bilirubin, creatinine

UNOS organ allocation

Repeatedly validated for predicting survival

Low means better prognosis, high means bad and you’ll get a transplant (>16 to benefit from transplant)

193
Q

When should you operate in a patient with cirrhosis

A

Never if you don’t have to–only for a liver transplant!

194
Q

Baclofen

A

GABA agonist that is an anti-spasmodic

Also used to reduce alcohol cravings!

195
Q

Portal hypertension

A

High pressure in portal vein due to resistance in liver from scarring

Classified as 12mmHg or higher (hepatic vein-portal vein gradient is normally <4mmHg)

Can lead to esophageal varices (that can rupture) and ascites (abd swelling, foot edema, shifting dullness)

196
Q

Approach to ascites

A

85% due to cirrhosis

Paracentesis despite coagulopathy (even if high INR and low platelets!) to do cell count and differential, SAAG (serum-ascites albumin gradient is >1.1 g/dL in liver ascites because liver ascites fluid has LOW albumin (gradient less when ascites due to peritoneal fluid because that has high protein!)), ultrasound

Consider transplant referral

Treatment: Na+ restricted diet (2g per day), NO protein restriction, oral diuretics every morning (spironolactone, furosemide), no NSAIDs or nephrotoxic meds

Diet and dual diuretics 90% effective, but for 10% refractory ascites do liver transplant, large vol paracenteses q 2 weeks, transjugular intrahepatic portosystemic stent-shunt (TIPS; shunt between portal and systemic circulations (within the liver!)), peritoneovenous shunt

Propanolol and ascites??

197
Q

Hepatorenal syndrome

A

Functional renal failure

Type I: precipitated by infection, GIB, etc; treat with IV albumin, octreotide, midodrine

Type II: mode of exitus in terminal liver failure; treat with liver transplant

198
Q

Hepatic encephalopathy

A

Second most common complication (28% over 10 years) of cirrhosis

Transient, reversible confusion, drowsiness

Asterixis, trail test, DON’T use ammonia to dx because no correlation with symptoms

Precipitating factors: dehydration, infection, GI bleed, narcotics, benzos, hypokalemia

Treatment: lactulose, rifaximin (or neomycin), no protein restriction

199
Q

Variceal hemorrhage in portal hypertension

A

Third most common complication (25% within 10 years) of cirrhosis

Usually esophageal varices bleed (occasionally gastric or ectopic varices)

Heavy lifting or NSAIDs can precipitate bleeding

Best prevention for esophageal varices is propanalol

To treat variceal hemorrhage, give octreotide (vasoconstrict) IV, packed RBCs, FFP, ceftriaxone/norfloxacin; endoscopic ligation (better than sclerotherapy), banding, rarely balloon tube, shunt/TIPS for refractory

200
Q

CYP3A inhibitors and inducers

A

CYP3A inhibitors (higher drug conc): azole antifungals, macrolides (clarithromycin, erythromycin, NOT azithromycin), cimetidine, grapefruit juice

CYP3A inducers (lower drug conc): rifampin, rifabutin, carbamazepine, ritonavir, St. John’s wort

201
Q

Drug induced liver injury (DILI)

A

Major reason for drug withdrawal from market

>50% of acute liver failure cases due to drugs (acetaminophen accounts for half of these)

Idiosyncratic drug reactions result in OLT or death 75% of the time

We don’t detect DILI more often because liver injury is infrequent

202
Q

Hy’s rule in hepatocellular injury

A

10% of DILI develop jaundice, and 10% of those die

So, 1% chance of death from ADR

203
Q

Definition of acute liver failure (ALF)

A

Note: not called fulminant hepatic failure anymore

Coagulopathy (INR >1.5) and any encephalopathy in a non-cirrhotic patient within period of 6 months

In clinical scenario we say if you become jaundiced and have hepatic encephalopathy within 6 weeks, would be ALF

204
Q

Therapy for acetaminophen toxicity

A

N-acetylcysteine (NAC) regenerates GSH (is a glutathione precursor) and buffers NAPQI to non-toxic metabolites if given promptly after APAP overdose

Use the Rumack-Matthew line using hours post-ingestion and APAP plasma concentration to determine who should/should not get NAC (the antidote)

No serious side effects of NAC!

205
Q

Mechanisms of drug-induced liver injury

A

1) Causes blebbing of hepatocyte membrane –> damage
2) Impeded bile flow –> cholestasis
3) Aberrant drug metabolism: slow vs. rapid acetylators, diff genotypes for CYP enzymes
4) Immune-mediated mechanisms of liver cell death
5) Leaking of mitochondria so mess up ability to do beta oxidation of fatty acids and respiratory chain (common in NASH)
6) Induce apoptosis

206
Q

Patterns of DILI

A

Hepatocellular: high ALT and AST but not as high alk phos, N/A/V, upper abdominal pain, onset within a few days and resolves faster, zone 3 necrosis, eosinophils, granulomas, steatohepatitis; this kind is more likely to kill you

Cholestatic: jaundice, itchy, severe nausea, high bilirubin and alk phos, cholestasis without cholangitis and no features of biliary obstruction

Remember that DILI is in differential for any LFT abnormality

207
Q

Where in the liver does drug damage start?

A

Drugs start damage around portal tract (this is where they come in) whereas fatty liver damage begins around central veins

208
Q

Patterns of drug-induced liver injury on histology

A

Triglitazone: apoptosis, fluffy cells

TMP-SMX: obliteration of bile ducts and inflammatory infiltrate

Isoniazid: apoptosis, lakes of bile because of cholestasis

Augmentin (amoxicillin-clavulanic acid): apoptosis and larger lakes of bile pools

Phenytoin: immunoallergic features (eosinophils), necrosis/death around portal triad

Diltiazem (and other Ca2+ channel blockers): granulomatous hepatitis

Tamoxifen: steatohepatitis

Didanosine in HIV: microvesicular steatosis because inhibits beta-oxidation of fatty acids and damages mitochondria

Acetominophen: liver destruction..?

Methotrexate and Vitamin A: fibrosis

Chemo agents: venoocclusive disease (rare, shows up after BM transplant and this is why treat BM tx pts with ursodiol)

Estrogen, androgens, MTX, aflatoxins, carbon tetrachloride: hepatic neoplasms

209
Q

Why are drugs in cirrhosis worse?

A

Reduced hepatic flow/portosystemic shunting: low 1st pass extraction, higher serum levels and bioavailability

Hypoalbuminemia: less protein binding –> increased serum concentration

Ascites/edema: increased vol of distribution for hydrophilic drugs

Portal gastropathy: altered drug absorption (either increased or decreased)

Loss of CYP450 activity: reduced clearance

Impaired biliary transport and/or renal excretion: increased serum concentration

Dose reductions in cirrhosis are recommended but no concrete evidence that CYP450 system doesn’t work as well in someone with normal liver

210
Q

Silymarin (Milk Thistle)

A

News says that milk thistle was good for treating Hep C, but wasn’t (no effect on ALT, HCV viral levels)

People now take milk thistle for Hep C, Hep B, NASH and say it subjectively improves fatigue, anorexia, nausea, general well-being, even though no evidence; also because people just like to take medicine

211
Q

Things that can cause acute liver failure vs. hepatocellular carcinoma

A

Acute liver failure: Hep A, Hep B, Wilson’s disease

HCC (and cirrhosis): hemochromatosis, steatohepatitis (NASH), Hep B, alpha1-antitrypsin deficiency,

Block 7: Endocrine, GI, Repro (5 decks)

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