DDx for jaundice framework for thinking DDx for unconjugated hyperbilirubinemia DDx for conjugated hyperbilirubinemia

Pre-Hepatic e.g. hemolysis Hepatic viral/toxic hepatic impairment Post-Hepatic bile duct obstruction UNCONJUGATED ↑ production (hemolysis) Liver cell damage (no uptake) ↓ conjugation (↓ UDP-glucuronosyltransferase) Congenital Gilbert’s (5% of people) » Crigler-Najjar Acquired: drug effect CONJUGATED Liver cell damage (limited MRP2 activity) Obstruction (stone or tumor) Decreased excretion (limited MRP2 activity) Congenital: » Dubin-Johnson » Rotor

Interpret low albumin labs.

Ref Ranges (4.0-6.0 g/dL = 40-60 g/L) Basis for Low Alb Decreased synthesis ?Increased catabolism poor nutrition (in that case, you'd expect INR to be normal or correctable with vit k supp; if not, likely liver dz) Assoc Dzs chronic liver failure Extrahepatic Cause Malnutrition Nephrotic syndrome, Protein-losing enteropathy, vascular leak, , malignancy, and inflammatory states

03-10 Liver Structure and Fxn Flashcards by Joseph Canarie

Major cell types (+ function) in the liver

Three major cell categories:

<ol>
<li>– Hepatocytes PRODUCTION
<ul>
<li>Organized in lamina of cell plates</li>
<li>metab fxns involving CHOs, fats and prots</li>
<li>bile production</li>
<li>biotransform Rx & toxins (make hydrophilic)</li>
<li>gets rid of bilirubin</li>
<li>storage</li>
</ul>
</li>
<li>– Cholangiocytes EXCRETION
<ul>
<li>Intercellular channels > bile canaliculi</li>
</ul>
</li>
<li>– Non-parenchymal cells FILTRATION
<ol>
<li>Kuppfer cells</li>
<li>Sinusoidal epithelial cells (leaky)</li>
<li>Hepatic stellate cells, a.k.a. Ito cells (collagen synth)</li>
</ol>
</li>
</ol>

How well did you know this?

Not at all

Perfectly

Describe the gross anatomy of the liver

<ul>
<li>Gross</li>
<li>Blood Supply</li>
<li>Biliary Tree</li>
<li>Lymphatics</li>
</ul>

GROSS:

<ul>
<li>Capsule (peritoneal): surrounds liver except “bare spot” of posterior aspect - continuity w/ retro-peritoneum</li>
<li>organ divided into segments by blood supply</li>
</ul>

BLOOD SUPPLY: Dual hepatic a. + portal vein

<ul>
<li>aorta→ celiac artery→ common hepatic a.→ r & L hep a.
<ul>
<li>OR</li>
</ul>
</li>
<li>aorta→SMA→RHA +</li>
<li>left gastric→LHA
<ul>
<li>R hep art→ cystic aa. to G.B.</li>
</ul>
</li>
<li>L, mid, and R hepatic vv.</li>
</ul>

BILIARY TREE

<ul>
<li>Canals of Hering→ bile ductules→ terminal bile ducts→ segmental bile ducts→ R + L lobar ducts→ common hepatic bile duct (see image)</li>
</ul>

LYMPHATICS

<ul>
<li>lymph forms in space of Disse</li>
<li>
Pleural effusion in the presence of massive ascites may be explained by lymph flow in trans-diaphragmatic lymphatics
</li>
</ul>

How well did you know this?

Not at all

Perfectly

Describe the microscopic anatomy of the liver.

<ul>
<li>Divided into ~hexagonal "classic lobules with CV at center and 6 peripheral hepatic triads OR</li>
<li>Divided into acina, the area surrounding a portal "triad" which contains:
<ul>
<li>proper hepatic artery</li>
<li>hepatic portal vein</li>
<li>common bile duct</li>
<li>lymphatic vessels</li>
<li>branch of thevagus nerve</li>
</ul>
</li>
<li>Blood supply diminishes as you go to outside of acinus</li>
</ul>

Hepatocyte arrangement

<ul>
<li>
Basal surface faces sinusoidal space, microvilli

Apical face adjacent cells, enclose bile canaliculi
</li>
<li>
Lateral from bile canaliculi > Disse’s space
</li>
</ul>

How well did you know this?

Not at all

Perfectly

Kartagener's syndrome involves what findings?

<ol>
<li>situs inversus</li>
<li>Bronchiectasis
<ul>
<li> </li>
</ul>
</li>
<li>chronic sinusitis</li>
</ol>

How well did you know this?

Not at all

Perfectly

Describe bilirubin production and excretion.

<ol>
<li>RBC breakdown: Hgb →Heme →Biliverdin →Bilirubin</li>
<li>Bilirubin transported in blood bound to albumin (unconjugated, lipidsoluble)</li>
<li>Bili taken up by hepatocytes</li>
<li>Bound to glutathione-s-transferase and then conjugated by bilirubinUDP-glucuronosyltransferase</li>
<li>conj bili (water soluble) →bile ducts via MRP2 transporter (or some back to blood)
<ul>
<li>some: bili—intest. bacteria→ urobilinogen→ reabsorb'd = eneterohepatic circulation (99%)
<ul>
<li>will be secreted by kidney</li>
<li>or urobilinogen —reduction→ stercobilin (gives poop brown color)</li>
</ul>
</li>
</ul>
</li>
</ol>

How well did you know this?

Not at all

Perfectly

DDx for jaundice

<ul>
<li>framework for thinking</li>
<li>DDx for unconjugated hyperbilirubinemia</li>
<li>DDx for conjugated hyperbilirubinemia</li>
</ul>

<ul>
<li>Pre-Hepatic
<ul>
<li>e.g. hemolysis</li>
</ul>
</li>
<li>Hepatic
<ul>
<li>viral/toxic hepatic impairment</li>
</ul>
</li>
<li>Post-Hepatic
<ul>
<li>bile duct obstruction</li>
</ul>
</li>
</ul>

UNCONJUGATED

<ul>
<li>↑ production (hemolysis)</li>
<li>Liver cell damage (no uptake)</li>
<li>↓ conjugation (↓ UDP-glucuronosyltransferase)</li>
<li>Congenital
<ul>
<li>Gilbert’s (5% of people)</li>
<li>» Crigler-Najjar</li>
</ul>
</li>
<li>Acquired: drug effect</li>
</ul>

CONJUGATED

<ul>
<li>Liver cell damage (limited MRP2 activity)</li>
<li>Obstruction (stone or tumor)</li>
<li>Decreased excretion (limited MRP2 activity)</li>
<li>Congenital:
<ul>
<li>» Dubin-Johnson</li>
<li>» Rotor</li>
</ul>
</li>
</ul>

How well did you know this?

Not at all

Perfectly

Describe liver metab of Rx

<ul>
<li>Phase I: cytochrome P-450 monooxygenase system (many) – Oxidation, Reduction, Hydrolysis, Hydration, Decarboxylation,

<ul>
<li>Isomerization</li>
<li>Variability: drug-drug, host factors, environmental factors</li>
</ul>
</li>
<li>Phase II: other enzymes
<ul>
<li>Glucuronidation, Sulfation, Methylation, Acetylation, Glutathoine conjugation</li>
</ul>
</li>
</ul>

How well did you know this?

Not at all

Perfectly

Describe liver metab of carbs

Carbs

<ul>
<li>Recall that G-6-P has 3 fates→
<ul>
<li>glycogen (2 days supply)</li>
<li>breakdown→ TCA</li>
<li>Pentose-Phosphate shunt</li>
</ul>
</li>
</ul>

Liver Makes Glucose via Gluconeogenesis

<ul>
<li>
glycogenolysis → glucose(liver has enough glycogen for two days' energy needs)
</li>
<li>
pyruvate, AAs, and FAs→ glucose
</li>
<li>
Lactatefrom muscle, intestine, liver, or RBCs→Cori cycle (see image here)
</li>
<li>
Alanine Cycle:

<ul>
<li>
Ala made by catab of muscle (muscle wasting during prolonged fasting)→ liver→ glucose→ back to muscle
</li>
</ul>
</li>
</ul>

How well did you know this?

Not at all

Perfectly

Describe liver metab of fats

<ul>
<li>the liver is the main site of fatty acid synthesis from excess glucose (mammary gland and to a lesser extense adipose do this, too [Wiki])</li>
<li>
the liver synthesizes and extracts a large number of apolipoproteins* to transport these lipids

<ul>
<li>
*contain TGs, phospholipids, cholesterol and its esters, and lecithins
</li>
</ul>
</li>
<li>
Recall that Cholesterol from food or made by liver is not a fuel source but a structural component of membranes and a steroid hormone precursor
</li>
</ul>

How well did you know this?

Not at all

Perfectly

Describe liver synthesis of albumin and clotting factors

<ul>
<li>What proteins are synthesized in the liver</li>
</ul>

<ul>
<li>Coagulation</li>
<li>Transport, such as albumin and iron binding</li>
<li>Protease inhibitors</li>
<li>Acute-phase reactants
<ul>
<li>group of proteins expressed during acute and chronic systemic inflammation</li>
<li>These proteins are assumed to play an important role in the host defense against tissue damage and infection.</li>
<li>Example: Fibrinogen aids in clot formation</li>
<li>Anti-proteases serve to protect normal cells from proteases that are released from necrotic tissues.</li>
</ul>
</li>
</ul>

How well did you know this?

Not at all

Perfectly

Interpret elevated AST (SGOT) and ALT (SGPT)

<ul>
<li>Ref Range</li>
<li>Basis</li>
<li>Assoc Dzs</li>
<li>Extrahep sources</li>
</ul>

Both Aminotransferaseselevated in "hepatic pattern"

Ref Ranges

<ul>
<li>ALT/SGPT 10-55 U/L</li>
<li>AST/SGOT 10-40 U/L</li>
<li>part of gluconeogenic pathway</li>
</ul>

Basis

<ul>
<li>
Leakage from damaged tissue into circulation (hepatocellular necrosis)
</li>
</ul>

Assoc Dzs

<ul>
<li>
Viral, autoimmune, toxic, Wilsons, ischemia, acohol, NASH etc.
</li>
</ul>

Extrahepatic Sources

<ul>
<li>ALT, relatively specific for hepatocyte necrosis AST: muscle (skeletal and cardiac), kidney, brain, pancreas, RBC</li>
</ul>

How well did you know this?

Not at all

Perfectly

Interpret alk phos (AP, AF) findings.

High alk phos + GGT is a biliary pattern

Ref Ranges

<ul>
<li>(ALP, AF 45-115 U/L: Catalyze hydrolysis of phosphate esters</li>
<li>3x higher in children due to bone growth</li>
</ul>

Basis

<ul>
<li>
Overproduction and leakage into serum (rise is delayed due to need for induction of enzyme)
</li>
</ul>

Assoc Dzs

<ul>
<li>
Marked elevations: extra- and intrahepatic cholestasis, infiltrating disease (e.g., tumor, MAC), occasionally alcoholic hepatitis
</li>
</ul>

Extrahepatic Sources

<ul>
<li>
Bone growth or disease (e.g., tumor, fracture, Paget's disease), placenta, intestine, tumors
</li>
</ul>

How well did you know this?

Not at all

Perfectly

Interpret bilirubin labs

Ref Ranges

<ul>
<li>
Total Bilirubin (0.0-1.0 mg/dL, 0,)
</li>
</ul>

Basis of elevation

<ul>
<li>
Decreased hepatic clearance
</li>
</ul>

Assoc Dzs

<ul>
<li>
Unconjugated: liver cell damage (no uptake, e.g. viral/drug/EtOH hepatitis), increase production (hemolysis), decreased conjugation (congenital: Gilbert's and Crigler-Najjar or acquired: drug effect), vascular (decreased flow to liver), or starvation
</li>
<li>
Conjugated: liver cell damage, obstruction (stone or tumor), or congenital (Dubin-Johnson and Rotor)
</li>
</ul>

Extrahepatic Sources

<ul>
<li>
Increased breakdown of hemoglobin (hemolysis, ineffective erythropoiesis, resorption of hematoma) or myoglobin (resulting from muscle injury)
</li>
</ul>

How well did you know this?

Not at all

Perfectly

Interpret elevated GGT

High alk phos + GGT is a biliary pattern

Ref Ranges

<ul>
<li>
Gammaglutamyl transpeptidase (gamma-GT 0-30 U/L):
</li>
</ul>

Enzyme Fxn

<ul>
<li>
catalyzes the transfer of gamma glutamyl groups of peptides such as glutathione to other amino acids
</li>
</ul>

Basis for Elevation

<ul>
<li>
Overproduction and leakage into serum (inducible by alcohol and dilatin)
</li>
</ul>

Assoc Dzs

<ul>
<li>
Same as for high Alk P (Marked elevations: extra- and intrahepatic cholestasis, infiltrating disease (e.g., tumor, MAC), occasionally alcoholic hepatitis)
</li>
</ul>

Extrahepatic Sources

<ul>
<li>
Kidney, spleen, pancreas, heart, lung, brain
</li>
</ul>

How well did you know this?

Not at all

Perfectly

Interpret low albumin labs.

Ref Ranges

Basis for Low Alb

<ul>
<li>Decreased synthesis</li>
<li>?Increased catabolism</li>
<li>poor nutrition (in that case, you'd expect INR to be normal or correctable with vit k supp; if not, likely liver dz)</li>
</ul>

Assoc Dzs

<ul>
<li>
chronic liver failure
</li>
</ul>

Extrahepatic Cause

<ul>
<li>
Malnutrition Nephrotic syndrome, Protein-losing enteropathy, vascular leak, , malignancy, and inflammatory states
</li>
</ul>

How well did you know this?

Not at all

Perfectly

Interpret increased PT/INR labs in the case of suspected liver dz

PT/INR is a sign of the production capability of the liver (like albumin)

Ref Ranges

<ul>
<li>Prothrombin time (10.9␣12.5 sec, PT)</li>
<li>International Normalized Ratio (INR) (0.9␣1.2)</li>
</ul>

Basis for Low Numbers

<ul>
<li>
Decreased synthetic capacity
</li>
</ul>

Assoc Dzs

<ul>
<li>Acute or chronic liver failure (unresponsive to vitamin K)</li>
<li>Biliary obstruction (usually responsive to vitamin K administration)</li>
</ul>

Extrahepatic Sources

<ul>
<li>Vitamin K deficiency (secondary to malabsorption, malnutrition, antibiotics)</li>
<li>consumptive coagulopathy</li>
</ul>

Interpret ammonia labs.

Ref Ranges

Basis

<ul>
<li>
Decreased hepatic clearance
</li>
</ul>

Assoc Dzs

<ul>
<li>
Chronic liver failure
</li>
</ul>

Extrahepatic Sources

<ul>
<li>
Hepatocaval shunting, Protein metabolism defect
</li>
</ul>

Liver imaging options.

<ul>
<li>xray: only shows hepatosplenomegaly and calcifications</li>
<li>U/S: good general screening test, good especially for eval biliary tree, can show blood flow w/ doppler
<ul>
<li>not useful in obese pts</li>
</ul>
</li>
<li>CT:
<ul>
<li>w/o contrast: fat infiltration, Fe deposition, and focal ∆s e.g. subtle calcification or hemorrhage.</li>
<li>w/ contrast: tumors/focal lesions</li>
</ul>
</li>
<li>MRI: especially good for MRCP</li>
<li>Angio</li>
<li>ERCP</li>
<li>
Percutaneous Transhepatic Cholangiography (PTC): contrasted fluoro w/ catheter directly in biliary tree

<ul>
<li>
Used if ERCP is impossible (after surgery or impaired access from small bowel, (e.g. tumor))
</li>
<li>
Disadvantages: cost, pain, rad, bleeding, perf, cholangitis
</li>
</ul>
</li>
<li>Biopsy
<ul>
<li>percutaneous</li>
<li>via laparotomy</li>
<li>transjugular</li>
</ul>
</li>
<li>Fibroscan: gives a number relfecting the amount of fibrosis/scarring
<ul>
<li>Can be used in place of biopsy in for staging hepatitis/cirrhosis</li>
</ul>
</li>
</ul>

Important physical exam findings in liver disease

<ul>
<li>Jaundice</li>
<li>Hepatomegaly</li>
<li>Splenomegaly</li>
<li>Spiders</li>
<li>Edema</li>
<li>Ascites</li>
<li>Asterixis etc.</li>
</ul>

Interpret what pattern you see here:

<ul>
<li>Example AST 678 ALT 542 AP 126 gamma-GT 49</li>
</ul>

High transaminases relative to alk phos and gamma-GT = hepatic pattern

<ul>
<li>predominantly damage to hepatocytes</li>
</ul>

Interpret pattern here:

<ul>
<li>
Example AST 47 ALT 23 AP 674 gamma-GT 499
</li>
</ul>

High alkaline phosphatase and gamma-GT relative to transaminases = cholestatic pattern

<ul>
<li>tends to reflectinjury to bile ducts</li>
</ul>

What does this pattern and time course suggest?

<ul>
<li>
Acute enormous elevation of transaminases (5000-10000), then lower 5 days later (300-500)
</li>
</ul>

Strong suggestion of ischemic liver injury ("shock liver")

<ul>
<li>Typical example: Patient after MVA with major bleeding and shock admitted to ICU</li>
</ul>

Patient has an acute elevation persistent for 2-3 weeks (transmainases 2000 - 4000), then coming down to 200 - 400, then after 2 months completely normal.

<ul>
<li>This pattern is typical for...?</li>
</ul>

Typical pattern in for example acute hepatitis A

Example: Patient age 72, with general malaise, fever and abn liver tests, pain in back: ALT 76 AST 47 Alkaline phosphatase 760.

<ul>
<li>What are your thoughts?</li>
<li>What lab would you check next?</li>
<li>How would you interpret those findings?</li>
</ul>

<ul>
<li>Unclear pattern, ?cholestatic?</li>
<li>Order GGT
<ul>
<li>If definitely high: a liver/biliary tract problem very likely. Could have cholangitis, a malignancy of pancreas or bile ducts</li>
<li>If normal could be bone fraction of AP with a bone metastasis of malignancy or an infiltrating process such as lymphoma</li>
</ul>
</li>
</ul>

You have a jaundiced patient with a bilirubin elevated at 3.4, but all other liver tests (AST, ALT, Alk Phos, albumin, PT/INR, NH3 etc.) are normal.

DDx?

It is usually predominantly unconjugated elevation that may reflect Gilbert's (silent t) syndrome

could also be hemolytic process

DDx for elevated AFP

Ref range is < 19ng/mL

HCC: Classic = hypervascular mass in cirrhotic liver and a high AFP of 34,000 ng/ml, pathognomonic for HCC. AFP typically continues to rise.
Can also reflect a regenerating liver (e.g. pt w/ HCV w/ AFPs fluctuating up into the 300-500 range)
Can also reflect other germ cell tumors
- But then you'd expect not to find any liver dz findings

DDx for Elevated CEA

Carcinoembryonic Antigen (CEA)

Usually thought of as a colon cancer biomarker
sometimes associated w/ cholangiocarcinoma

Interpretation of an elevated Carbohydrate Antigen 19-9 (CA 19-9)

Associated w/ cholangioncarcinoma (as is CEA), but can also go up temporarily in cases of non-malignant cholangitis

LAbs to order for suspected hemochromatosis

iron
TIBC
iron saturation
ferritin
HFE gene assay: C282Y and H63D mutations

Labs to order to suspected a1AT

A-1-AT level
Phenotype (Pi type)

Test to order for suspected cases of Wilson's dz

ceruloplasmin
24 hour urine copper (+/- penicillamine challenge)

Tests to order when working up NAFLD/NASH

TSH
Lipid panel
HgbA1c
ferritin

Autoimmune liver disease work-up labs

Autoimmune Hepatitis Type 1:
- ANA, SMA SPEP (globulins)
Autoimmune Hepatitis Type 2:
- LKM (anti-liver kidney microsomal Ab)
Primary Biliary Cirrhosis:
- AMA (anti-mitochondrial antibody) IgM)
Primary Sclerosing Cholangitis:
- pANCA

Where in bodies do we get ammonia from?

What is it broken down into?

In which section of the liver (microscopic anatomy level) does this break down occur?

What happens to a patient w/ high NH3?

breakdown of AAs in our bodies → NH3

Periportal zone is where urea cycle converts NH3 to urea

If not working: encephalopathy

Why might you see thrombocytopenia in a patient w/ liver dz?

increased resistance to portal flow →
diversion to spleen (also varices, etc.) →
splenomegaly →
splenic sequestration of platelets