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Why is assessing the health of the liver important?

- Health of the liver is important for: 

1. Prognosis: important that pts and families know and understand severity/prognosis

2. Operative risk: pt survival of certain elective sxs may be affected by degree of liver func, helping guide tx decisions/risk assessment  

3. Eligibility for transplantation: have to be sick enough they would live longer with a transplant than without one

- REMEMBER: the liver can regenerate


What is the best biochemical (or other) test of liver disease?

- No easy measure of hepatic clearance or function

- No highly sensitive or specific test for underlying liver disease

- Liver is a silent organ associated with often non-specific symptoms (such as fatigue)

- All biochemical tests have limitations in predicting function and prognosis 

1. Symptoms, physical findings, and lab work have limitations in liver disease assessment 


What are some of the complications of liver disease (4)?

- Synthetic impairment: like est. function of a factory

1. Albumin

2. Clotting factors

- Cholestasis: impairment of bile flow

- DEC clearance: bilirubin

1. Few clinically useful hepatic clearance tests (Lidocaine): partially due to wide bell-shaped curves in healthy and unhealthy livers 

- Portal HTN: portal blood shunted around liver and not processed by it, leading to complications


What do LFT's measure?

- Often biochem measures of hepatocellular injury or death, or impairment of bile flow (i.e., ALT, AST, alk phos)


What are the true liver "function" tests?

- Those that measure clearance (bilirubin) or synthetic activity (albumin)


Provide examples of liver chemistries that detect injury, measure clearance, and test synthetic capacity.

- DETECT INJURY: aminotransferases (ALT, AST) & alkaline phosphatase

- MEASURE CLEARANCE: bilirubin, ammonia (can build up in the blood due to cirrhosis, and cause neurological effects) 

- SYNTHETIC CAPACITY: albumin, clotting factors made by the liver (simple blood test for evaluation of liver function)

1. Cholesterol: LATE COMPLICATION of severe dysfunction -> don’t depend on this one; not a great indicator of prognosis


What do aminotransferases measure? Which is more specific for liver injury?

- Aspartate aminotransferase (AST)

- Alanine aminotransferase (ALT)

- INC associated with cell injury or death

1. AST elevation also INC with muscle injury

2. ALT more specific for liver injury

- Marked elevations assoc w/1o hepatocellular injury


What does alk phos measure? In what benign conditions can it be elevated?

- Enzyme derived from bile ducts and correlates with intrahepatic and extra-hepatic injury or obstruction

1. Hard to tell if it is in tiny branches or the trunk: need imaging

- Level associated with INC synthesis -> INC when bile NOT flowing through bile ducts 

1. Can be high in pregnancy, growing children, teenagers

- Three important iso-enzymes: gut, liver, bone 


What dose cholylglycine measure?

- Serum bile salt

- Correlates with degree of cholestasis, intrahepatic or extra-hepatic obstruction to bile flow

- Cholestasis = impairment of biliary flow 


What does GGT measure? Clinical utility?

- Gamma glutamyl transferase/transpeptidase (GGT): enzyme in many tissues, including biliary ductules

- INC with cholestasis, biliary obstruction

1. Also INC with induction by many chemicals, ie Phenytoin (Dilantin: anti-convulsant) and ethanol

- So many meds and chemicals induce GGT that it is LIMITED CLINICAL UTILITY: not a great test

- Isolated GGT elevation is often due to medications or ethanol, rather than liver injury


What do you see here?

Icteric sclera


What does bilirubin measure? Benign elevation?

- Level represents a balance between input and hepatic removal -> imperfect measure of hepatic clearance and excretory function

1. Some pts w/cirrhosis have normal bilirubin, but when high, it is important

- INC with impaired clearance by the liver or w/intra-hepatic and extra-hepatic obstruction 

- Helps advise for prognosis, operative risk, and transplantation

- BENIGN ELEVATION (2-3 range): Gilbert’s syndrome (not that uncommon) -> transport problem, often when fasting (jaundiced post-call, for example) 


What does ammonia measure?

- Estimate of nitrogenous waste

- Detoxified in liver by the urea cycle and glutamine synthetase reaction

1. In chronic liver disease, DEC function and porto-systemic shunts around the liver

- Often, but not perfect correlation with hepatic encephalopathy: loss of brain function when a damaged liver doesn't remove toxins from the blood


What are the most important synthetic function tests?

- Prothrombin time (PT): prolonged when clotting factors I, II, V, VII, X deficient (VIII not made by liver) 

1. Prolonged when Vit. K deficient 

2. Correlates well w/hepatic synthetic func 

- International standardized ratio (INR)

Albumin: 1/2-life about 20d, hepatic synthesis

1. Rapidly changed w/acute illness, malnutrition (which many of these pts have), but still a good test  


How could this have been prevented?

- Pt should have received IV injection (instead of IM)

1. Bruise from injection

- Delayed prothrombin time (PT) 



What happened here?

- Pt. bled into thigh after arterial blood-gas because delayed PT 


What are the components of the Child Pugh score (table)?

- 1 is normal bilirubin and normal PT/INR

- Encephalopathy: ammonia

- Combo of measurements to assess how things are working: least is 5 and most is 15 -> higher = worse prognosis

1. Grade A: 5-6 

2. Grade B: 7-9 

3. Grade C: 10-15

- Probably don't need to know all of these details...


What are the parameters of the Model of End Stage Liver Disease? What is it used for?

- INR: standardized measure of prothrombin time (PT), hepatic synthetic function

- Bilirubin 

- Creatinine: when this goes up, things aren’t looking good in regards to prognosis -> DEC muscle mass due to malnutrition (leading to low creatinine), so if HIGH = poor prognosis

- This msmt gives you a feel for 3-6-mo prognosis; MELD of 25-30 not good for those who want to make it to the next year

1. Has to be 15 to get on transplant list: this # is what determines priority 



What can you conclude from all of this?

- Biochemical tests can give estimates of hepatocellular injury, cholestasis and function

1. No perfect test; all have limitations

2. No accurate hepatic clearance test

- Improved measures of staging pts and estimating prognosis and surgical mortality

1. Pugh

2. MELD: has to be 15 to get on transplant list (this is what gives priority on this list) 


What is going on here?

- Variceal bleeding: endoscopy of distal esophagus with massive amt of blood flowing

- Distended vein bleeding as aggressively as arterial hemorrhage, but with no pulsation (like a garden hose) 

- People can rapidly bleed to death with variceal bleeding: engorged, distended veins

1. Most feared complication of portal HTN 


What is the breakdown of blood flow to the liver?

- 30% hepatic artery

- 70% portal vein:

1. Splenic vein

2. Splanchnic circulation


How can cirrhosis cause portal HTN?

- Pressure = flow x resistance 

1. Resistance to flow + INC flow = INC pressure in the portal vein 

- Cirrhosis INC pressure in the veins going to, and around the liver by INC resistance

1. Fibrosis (scarring) w/distortion of vasculature

2. Live usually like a sponge, but sinusoids (low resistance to flow) changed to capillaries (higher resistance): CAPILLARIZATION 

- INC blood flow to stomach and intestines


What is the pathogenesis of chronic portal HTN?

- Pressure in portal vein – pressure in hepatic vein is the gradient: cirrhosis INC this gradient, leading to shunting around liver

1. Portosystemic shunting: shunts around the liver to the heart -> goal of the RBC

- Chemicals (vasoactive peptides) in splanchnic blood supply get in systemic system (like glucagon, a vasodilator) b/c no longer filtered by the liver

1. Really 2 circulations: systemic and portal/splanchnic

- Peripheral artery dilation: systolic BP may be 98 or 100 -> arteries to stomach and intestines dilated, so less resistance to flow in splanchnic arteries, leading to INC splanchnic blood flow, creating the problem 


What collateral veinous systems become congested in portal hypertension?

- Venous collaterals form from distal esophagus (azygous system) to rectum

1. Hemorrhoids: esp. after delivering babies (bothersome, but small; can get massive)

- ANTERIOR collaterals via umbilical vein: re-canalization of venous channels in navel, flowing on anterior abdominal wall back to the heart

- POSTERIOR collaterals via retroperitoneal veins, splenorenal shunts -> these collaterals exist, but we don't use them; if splenic v. under high pressure, spleen enlarges/distend, collaterals will form/open

1. Splenic vein is portal

2. Renal is systemic 

-NOTE: blood will go the way of least resistance 


What are varices?

- Torturous venous collaterals under high pressure underneath esophageal mucosa 

- 50% of newly diagnosed cirrhotics

- INC up to 8%/year, and 32% bleed within 2 yrs

- Major cause of death: when these bust, it is a medical emergency

1. Tell pts: if you vomit blood, or have melena, come to ER immediately 


What are 2 complications of liver injury that make varices especially dangerous?

- High-pressure bleeding

- THROMBOCYTOPENIA: blood has trouble leaving the spleen, so PLT’s get caught here and don’t last as long

1. Normal PLT count: 100,000-150,000

- COAGULOPATHY: synthetic impairment of clotting factors -> lower production in cirrhosis (INR is a measure of liver function)

- IMAGE: blood in distal esophagus right at GE junc; high pressure from distended vein to stomach 


What do you see here?

- Esophageal varices at GE junction; black is the stomach

1. PLASMA coming out: hardly any circulating red cells b/c Hct so low

- This happened b/c pt could not get adequately transfused due to Ab’s to blood donations

- NOTE: when a liver pt vomits blood, take it SERIOUSLY 


What is going on here?

- Tx for esophageal varices: suctioning up vein, and putting rubber band on it endoscopically (banding)


What do you see here?

- Portal hypertensive gastropathy: chronic source of bleeding (sometimes rapid bleeding)

- Congestion of stomach mucosa that gives mosaic pattern: portal HTN

1. Blood congesting submucosal area 

- May experience bleeding from the stomach, which may uncommonly manifest itself in vomiting blood or melena

1. Similar pattern to GAVE, but in the whole stomach, whereas GAVE tends to be in antrum/lower stomach 


What is this?

- Portal hypertensive gastropathy: blood oozing from congested mucosa in body, antrum -> multiple punctate bleeding spots

- Steady oozing of inside lining of the stomach 


How can you treat portal HTN?

- Volume resuscitation

- Correct coagulopathy: Vit. K subcu to try and lower INR

1. Fresh frozen plasma with clotting factors

- Splanchnic vasoconstriction: try to constrict arteries to stomach/intestine, DEC blood flow to stomach, & indirectly DEC blood flow via collaterals

1. Don’t want to do too good a job, or you will get ischemic stomach or intestines -> do this gently: just enough to DEC blood flow

- DEC blood flow to stomach and intestines

- DEC blood flow via collaterals

- Vasopressin: vasoconstrictor 

Somatostatin (Octreotide): blocks endogenous vasodilators (i.e., glucagon), and much safer than vasopressin 


What is the prognosis with esophageal varices?

- BAD: these stats are from 1981

- Mortality 42% w/in 6 weeks

- 60% of early deaths due to bleeding

1/3rd of pts had rebleeding within 6 weeks

- 1 year survival 34%


What is the tx for esophageal varices?

- Endoscopic tx to sclerose or BAND (tx of choice) the varices

- DEC portal pressure:

1. Beta blockers: chronic use -> selectively DEC blood flow to stomach, intestines, and collaterals (non-selective like Propranolol)

a. Prevent re-bleeding 

2. Transjugular intrahepatic portosystemic shunt (TIPS)

3. Liver transplant: any pt with complications of portal HTN

4. Surgical portosystemic shunt: often very high risk, and we try to AVOID this


What are the elements of the child Pugh classification (5)?

- Albumin 

- Prothrombin time (INR) 

- Bilirubin 

- Ascites 

- Encephalopathy 

- REMEMBER: child A (6), B (9), and C (15) from good to bad prognosis (97-62%) -> this is key for evaluating for transplant and definitive tx 


What is the pathophys of ascites?

- Free fluid in the abdominal cavity -> can be 12-14L 

- INC resistance to portal veinous flow + INC flow to portal vein (INC flow to stomach, intestines) 

- INC lymphatic flow (and resistance) -> leakage of lymph flow from liver, intestines in peritoneal cavity 

1. We all have a little fluid here, but not clinically detectable 

- INC portosystemic shunting of vasodilators due to INC resistance to flow

1. Systemic vasodilation: BP 98, but fingers are warm because vasodilated peripherally 

- DEC renal perfusion: INC renal vasoconstriction, INC RAS, and INC Na+ reabsorption 

1. Kidneys focused on themselves, and do not think about/know about the big picture 


How does ascites affect the kidneys?

- Ascites -> DEC effective volume (via systemic vasodilation) -> renal Na+ retention -> ascites + edema 

- Nobody really knows how this happens, but probably a combo of the all of these things 


How does the kidney respond to ascites?

- Left side of the image is the point 

- Vasodilated systemic system, but same # of blood cells -> this looks like less effective volume

- INC renin, Ang II, aldosterone, and tubular reabsorption of Na, and DEC excretion of Na by the kidneys 


How can liver disease damage the kidneys?

- DEC renal clearance

- Severe liver disease associated w/Na+ retention and DEC creatinine clearance

- Hep C can cause renal disease independently: 

1. Membranous glomerulonephritis

2. Membranoproliferative glomerulonephritis 

-Kidneys impacted by the severity of liver disease

1. Even good kidneys don’t work as well when the liver is sick 


Why is all this fluid in the abdominal cavity (ascites) important?

Tense ascites: pressure on diaphragms, stomach, leading to difficulty breathing and eating

- Hepatic hydrothorax: fluid can go superiorly; it will go the way of least resistance (pleural effusion)

- Spontaneous bacterial peritonitis: infection -> un-drained, low protein fluid is like a giant petri dish

1. Transient bacteremia can get through intestinal wall (G- rods usually), infect 10L fluid, and cause spontaneous bacterial peritonitis 


What is going on here?

- Umbilical hernia due to massive ascites

- Blue veins from umbilical vein going back to heart


What is this? Tx?

- Massive ascites with blue veins flowing back to the heart from the umbilical vein

- Urgent paracentesis to draw fluid off: looks like it is about to explode

1. Never want to get your navel to this size

2. Skin so stretched that there is black eschar 

- NOTE: rash is unrelated in this case 


What do you see here?

- FLOOD SYNDROME: spontaneous umbilical rupture in portal HTN with massive ascites

- Need emergency operation to fix this umbilical hernia 


What is spontaneous bacterial peritonitis?

- Large amount of undrained fluid

- Low protein ascites

- Low complement

- Bacterial translocation from intestines to blood

- Transient bacteremia infects the ascites


How is ascites treated?

- Sodium restriction: not easy

Diuretics: to try to get rid of Na -> telling kidneys to let Na+ go

- Treat the liver disease: hopefully, replace the liver

1. Liver transplantation: Memphis a transplant center

- Large volume paracentesis: give IV albumin (6-8g) at the same time (Univ. of Barcelona)

- Correct the portal hypertension:

1. Transjugular portosystemic shunt (TIPS)

2. Surgical portosystemic shunt: quite limited


What does survival look like with refractory ascites?

- Can take fluid off safely, but survival for pts with ascites not responding to medical therapy terrible

- Think about transplantation with these guys 



25-y/o Native American woman presenting with jaundice and epistaxis. Bilirubin 12, AST 210, ALT 88, Alk phos 128, PT 18, and INR 1.8.

What might be going on?

- Dying at 25 from alcoholic liver disease: case example from class

- Up to 41% of liver disease in Native Americans alcoholic liver disease: as high as 65% of all deaths from chronic liver disease in this population

- More F Native Americans have drinking problems than other groups, but disease affects all ethnicities  


Epi of ethanol use and alcoholic liver disease in the US?

- ETHANOL USE: 63% >18 drink ethanol

1. Top 20% of drinkers drink 80% of ethanol and top 2.5% drink 27% of ethanol

2. Alcohol dependence/abuse 7.4%: 11% of M, and 4% of F

- ALCOHOLIC LIVER DISEASE: 24% of chronic liver disease and 40% of deaths from cirrhosis 

- NOTE: alcohol, by itself, is not that big of a picture in liver disease, even though this is the thing most people think about: often alcohol + something else that gets people into trouble 


What are the main causes of chronic liver disease in the US?

- Hep C: 57% 

- Alcohol: 24% 

- NAFLD: 9% 

- Hep B: 4% 

- Other: 6%


What are the (3) manifestations of alcoholic liver disease?

- STEATOSIS: many of us probably had this in college

- Alcoholic HEPATITIS

- Alcoholic CIRRHOSIS: advanced fibrosis and regenerative nodules -> takes years 

1. HCC, cholangiocarcinoma


What kind of drinking puts you at risk for alcoholic liver disease? Questions you should ask?

- Ethanol >40-80gm/d for >5yrs duration, or about 6 drinks/day

1. Women and men clearly differ: takes much less for F to have alcoholic cirrhosis risk (see attached image) 

- Alcoholic beverage: 12 gm

1. 12 ounce bottle beer: some pts don't think of this as an alcohol 

2. 4 ounce glass of wine

3. one ounce of liquor

- Size of the drink important: good to quantify what they are drinking -> may ask how long a 5th of rum lasts, for example 

- Key thing is asking in a non-judgmental way

- Having family members in the room can help too (because they may help the pt be more honest) 


Do all alcoholic get liver disease?

- No 

- Actually, only about 10% 


Why the difference in men and women (alcoholic liver disease)?

- As little a 3 drinks/d in women

- Differences in volume of distribution: sometimes it's just body build

- DEC gastric alcohol dehydrogenase activity, esp. in younger adults

- Differences in first pass metabolism



What are the clinical features of alcoholic hepatitis (incl. labs)?

- Typically, 40-60-y/o and >80mg/d for >5yrs (often 100gm/d; 6-7 drinks)

- Rapid onset of jaundice + fever, muscle wasting, and ascites (can even present with this)

1. Hepatomegaly with tenderness b/c: left lobe will selectively regenerate before the right, and steatosis (fatty infiltration) 

a. Liver normally about 11cm along right costal margin

2. Fever can be a confusing symptom b/c they don’t have active infection (possible aspiration pneumonia w/alcoholics -> rule out infection)

- AST, ALT rarely over 300 (important for exam); will have elevated INR

1. If it’s over 300 (esp. over 1,000), think of something else: Hep B, cocaine, Tylenol OD

2. AST > 2x ALT

- Frequent leukocytosis: peripheral blood will have a high white count

- Prevalence unknown, but pproximately 20% of 1604 alcoholic patients undergoing liver biopsy will have evidence of alcoholic hepatitis 


What do you see here?



What is this image illustrating?

- Hepatomegaly: palpable below costal margin

1. Can feel left lobe: left will selectively regenerate before the right lobe 

- Splenomegaly 


What is the risk of cirrhosis with alcoholic liver disease?

- Steatosis -> steatohepatitis -> cirrhosis 

1. 1% risk if  > 30-60 gm/d

2. 5.7% risk if  > 120 gm/d


What is the pathogenesis of ALD cirrhosis?

- Many proposed mechanisms of ethanol-induced injury

- Few animal models

- No one theory accepted


How are genetics involved in alcoholic liver disease (ALD)?

- Concordance rate for alcoholic cirrhosis 3x higher in monozygotic twins than dizygotic (regardless of fam envo in twins separated at birth

- East Asian: functional polymorphisms of ADH2*1 gene associated w/INC susceptibility to ALD

1. Flushing with acetylaldehyde exposure 

- Caucasians: only replicated assoc TNF α-238 polymorphism and ALD 

- More than just a bad habit

- Alcoholism and alcoholic liver disease run in families


What are the mechanisms of ALD?

- Ethanol and acetylaldehyde cause intestinal injury and INC permeability, resulting in endotoxemia

- ENDOTOXEMIA results in an inflam response by Kupffer cells -> leukocyte chemokines, cytokines involved in hepatocyte apoptosis and necrosis 


What is the two-hit theory of ALD?

- First hit: FATTY LIVER (weakened liver)

1. Oxidative stress

2. ↑NADH/NAD ratio 

3. Obesity and DM: genetics/diet 

4. Fat sensitizes liver to 2nd hits

- 2nd Hit: INFLAM and NECROSIS

1. Oxidative stress, hypoxia, immunological rxn


What are the 3 predictors of survival for alcoholic hepatitis?

- Maddrey Score

- Glasgow Alcoholic Hepatitis Score

- Model for End-Stage Liver Disease (MELD)


What is the Maddrey score?

- Modified discriminant function: factors in PT and bilirubin 

1. > 32 implies one-month mortality 35-45% (even with abstinence) -> there are cancers with a better one-month survival than this 

- These people NEED TO ABSTAIN

- Score helps express seriousness to pts and families 


What factors are included in the Glasgow Alcoholic Hepatitis score?

- Age

- WBC on presentation 

- BUN 

- INR 

- Bilirubin 

- Higher the score = less likelihood of survival (9 is the cutoff)


What is the cutoff for the Glasgow Alcoholic Hep score?

- 9 is the cutoff here

- This includes medical intervention 


What are the factors in the Model of End Stage Liver Disease (MELD)?

- INR 

- Bilirubin 

- Creatinine

- For test purposes, KNOW THIS

- This is how we measure prognosis 

1. As MELD score goes up, 90-day mortality goes through the roof: this is critical 


What are 3 liver diseases can make alcoholic hepatitis worse?

- Hepatitis C: high prevalence in ALD w/risk factors like transfusion b4 1992, cocaine, IVDU

- Hemochromatosis: ethanol assoc w/advanced fibrosis w/HFE -> INC cirrhosis and shorter survival 

1. HFE heterozygosity may also play a role

- Alpha one antitrypsin deficiency: also some overlap here -> double hit b/c genetic condition + alcohol (if ALD)


What is this?

- Prussian blue iron stain: hemochromatosis 

- Regenerating nodules and lots of scarring 



What do you see here?

- PAS stain highlights red hyaline globules characteristic for AAT deficiency

- 1/50 white blood donors have this heterozygosity 


What are the most important envo factors determining ALD risk?

- Ethanol patterns

- Obesity: most common double hit in the US

- Associated hyperglycemia



What is the tx for ALD?


- Optimize NUTRITION: these pts can look like they have kwashiorkor -> careful supplementation with 2,200 calories/day

- Pentoxifylline (TNF α inhibitor)

- Immunosuppression with CCS: to DEC inflam in select pts

1. Meds without nutrition often don’t work 


Can ALD pts get liver transplants?

- Yes, but very strict guidelines about alcoholics: have to go through rehab, AA, abstinence, generally for 6 months 

- If they pass these hurdles, a lot of them are easy after that -> a lot of them never, ever drink again, and these people do pretty well, and live fruitful lives (both 1- and 5-yr survival above 88%)

- Transplant board is the judge and the jury in these cases: if they turn pt down, they can get an opinion from another center (in some situations, they will make exceptions in under 6 months) 


What inflammatory cells are involved in hepatitis?

- Usually a mixture of neutros, lymphos, and macros

- ALD: progression of fatty change, inflammation, and fibrosis

- Other random stuff: 

1. Micro and macro are a spectrum: micros coalesce, and become macro, pushing nucleus to the side of the hepatocytes

2. Fatty starts to become yellow, enlarged, and soft 


What are some of the hepatocyte and parenchymal responses to ALD?

- Can undergo a # of degenerative, but potentially reversible changes, like accumulation: 

1. Fatty liver: steatosis (left); still reversible after a few days of abstinence

2. Bilirubin: cholestasis (right); bile plugs with brownish/green color


Where do the changes in alcoholic liver disease begin?

- In the centrilobular acinus zone 3 (lower oxygen tension here): extend outward towards portal tracts 

1. Most blood supply in zone 1, so changes start around central vein 

- Macroscopically, fatty liver in pts w/chronic alcoholism is a lg (4-6kg), soft organ that is yellow and greasy




What is the pathogenesis of ALD?

- Alcohol causes steatosis, dysfunction of mito and cellular membranes, hypoxia, and oxidative stress 

1. Even in small amts (millimolar conc), alcohol directly affects microtubular and mito func and membrane fluidity 

- Hepatocellular steatosis results from: 

1. Shunting of normal substrates away from catabolism and toward lipid biosynthesis due to INC generation of NADH by 2 major enzymes of alcohol metabolism, alcohol dehydrogenase and acetaldehyde dehydro

2. Impaired assembly and secretion of lipoproteins

3. INC peripheral catabolism of fat, releasing free fatty acids into the circulation 


What is this?

- Macrovesicular steatosis assoc with hepatocyte ballooning (lg, fluid membrane) and Mallory bodies:

1. Hepatocyte swelling and necrosis 

2. Mallory-Denk bodies: tangled intermediate filaments with other ubiquinated proteins, characteristic, but NOT specific (pink, hyaline material)

3. Inflammatory rxn: can be tricky to pick up in liver (all the little black dots)  

- Most forms of viral and autoimmune hepatitis do NOT feature steatosis (unlike ALD, and NAFLD)

- INC in fatty acids 



- Mallory-Denk bodies (ALD): tangled intermediate filaments with other ubiquinated proteins

- Characteristic, but NOT specific for ALD 

- Pink, hyaline material


What is going on here?

Perivenular fibrosis: alcoholic hepatitis can lead to activation of sinusoidal stellate cells and portal fibroblasts, giving rise to fibrosis 

1. Fibrous septa act as bridges bt centrilobular regions and portal tracts w/devo of cirrhosis 

- Perivenular fibrosis is earliest pattern of hepatic fibrosis in ALD

1. Fibrosis not always esp. specific to ALD, but does have central, perivenular pattern

- Encases hepatocytes, so you get a chicken-wire appearance, and nodular appearance as chicken-wire comes together 

- Trichrome stains for the fibrosis (see attached)

- Steatosis in the background


What happened here?

Micronodular cirrhosis: regenerative nodules quite sm, averaging <3mm in size 

- MCC is chronic alcoholism, and cirrhosis devos over many years 

- NOTE: micronodular cirrhosis may also be seen with Wilson's disease, PBC, and hemochromatosis


What do you see here?

Micronodular cirrhosis: seen with moderate fatty change (macrovesicular steatosis) 

- Regenerative nodule surrounded by fibrous CT extending between portal regions 

- Aggregates of inflammation: blue in background

1. Fibrosis: pink

-This is NOT specific -> can also be seen with Wilson’s, PBC, and hemochromatosis 


What is this demonstrating?

- Reversal of cirrhosis: only 10-15% of alcoholics devo cirrhosis, and it can be reversible 

- Hepatic steatosis may cause hepatomegaly, with mild elevation of serum bilirubin and alk phos, but severe hepatic dysfunction is unusual 

- Risk of HCC in alcoholic cirrhosis 1-6% annually

- Note the regeneration on the right: many more hepatocytes (front image)

- TOAST: AST is higher in alcoholics

- VirALT: ALT is higher in viral 


What is genetic hemochromatosis?

- Most freq genetic condition in Caucasians (1:200-250 ppl of Celtic/Nordic descendence) 

1. Not everyone with genetic predisposition has iron overload, and some people have overload w/o genetic predisposition

- Most common type (1) related to HFE gene muts

1. Inappropriately INC uptake of dietary iron

2. Serum Iron off-loaded into tissues with high transferrin receptors: liver, heart, pancreas, and thyroid 

3. INC oxidative stress generates FREE RADICALS


What is hepcidin?

- Principal iron-regulatory hormone

Inverse relationship bt hepcidin & iron absorption: hepcidin induced by excess iron, and DEC w/iron deficiency 

- Regulation of hepcidin release is central mech in pathogenesis of hereditary hemochromatosis (HFE)

- Expressed predominantly in hepatocytes

- Binds to ferroportin on basolateral surface of enterocytes and macros

1. HFE = less hepcidin = more iron absorption


Is iron deficiency in adults typically a diet problem?

- No, more likely to be from iron loss, via: 

1. GI, 

2. Pregnancy, 

3. Menstruation, etc. 

- System usually corrects, but if there is enough iron loss, body can get behind 


What is the hereditary hemochromatosis gene? Mutations?

- HFE gene = High Fe

- 85-90% due to muts in this gene: 

1. C282Y: missense mut (tyr for cys) -> homo in most pts w/HH

2. 10-15% don't have abnormal HFE -> clinically important bc pt may have hemochromatosis & NO mut (don't fall into this trap)

3. C282Y/H63D or C282Y/S65C may be assoc with iron overload (other homo gene muts NOT associated with iron overload) 


What is wrong with HFE in HH?

C282Y (most common): cysteine to tyrosine 

- Abnormal HFE protein may lead to DEC sensing of actual iron stores, leading to excess iron absorption in the DUODENUM (remember - 2+ ions absorbed here)

1. DEC hepcidin expression, leading to up-regulation of ferroportin 


What are Fe and hepcidin levels like in iron excess, iron def, and HFE defect (image)?


What are the clinical features of hemochromatosis?

- Phenotypic expression in 70%, but end-organ damage in only 10% 

- Adult-onset: >40yrs M, >50 yrs F (later dx in F due to menstruation) 


1. General: fatigue, arthritis (most common)

2. Liver: cirrhosis, HCC

3. Heart: Restrictive cardiomyopathy

4. Skin: hyperpigmentation

5. Pancreas: diabetes (“bronze diabetes”)

6. Arthritis: second/third metcarpal-phalangeal joints 

- Think about this in pts w/underlying liver disease and diabetes, or CHF

- Can have differential timing of effects in different organs: may not present with all of these symptoms


What are the other types of hemochromatosis?

- T2 (juvenile): excess iron due to lack of hepcidin (mut at HAMP and HJV genes) 

1. Age of onset: 10-15yrs, and more cardiac involvement (image) 

- T3: transferrin receptor mut 

- T4: ferroportin muts -> DEC ability to export Fe out of hepatocytes 

- NOTE: just remember these exist (don't memorize)


How do you diagnose hemochromatosis?

- EXCESS PLASMA IRON: calculate iron saturation via serum iron/serum transferrin x 100 = transferrin saturation; >45% = suspect iron overload 

- EXCESS STORAGE of iron: measure serum ferritin; >1,000 mcg/L predicts advanced fibrosis/cirrhosis 

1. Ferritin can be elevated in pts w/HCV, HBV, NASH

- HFE GENE TEST: homo C282Y mut -> confirms diagnosis (85-90% of genetic cases have this mut)

- LIVER BIOPSY: less important now that we have gene test, but can help determine whether pt has advanced cirrhosis/fibrosis 

1. HIC/age > 1.9 = excess tissue iron (hepatic iron index) 

2. Assess degree of liver injury in pts with abnormal LFTs and Ferritin > 1000

3. Diagnose hemochromatosis in the absence of HFE mutation (type II, III)


What is the difference b/t these two images?

Prussian blue: stain for iron 

- LEFT: hemochromatosis -> will typically be in nodules, but not areas of fibrosis 

- RIGHT: secondary iron overload due to hemolytic anemia or transfusions 


What is the difference here?

- Right shows liver completely iron overloaded (compare to spleen, which should look about the same "color") 


- SQUID = superconducting quantum interference device

- NOTE: image on left is normal 


Who should be screened for HFE? How?

- Recommended for all first degree relatives

1. Check Ferritin/TS and HFE mutation analysis

2. For screening kids, sufficient to check other parent; if normal then children are hetero, and do not need further testing


Tx for HFE?

- Focus on removing excess iron, regardless of mut

- PHLEBOTOMY: may need several wks, even yrs

1. Until ferritin is <50ng/mL

- IRON-CHELATING AGENTS: bind iron, & remove via urine (mostly not required)

1. IV desferoxamine or oral deferasirox: useful when patient has low hemoglobin (sickle cell, thalassemia)

- AVOID VIT C: INC Fe absorption

- DEC ALCOHOL intake


What are some secondary causes of iron overload?

- Ineffective erythropoeisis: thalassemia, sideroblastic anemia 

- Parenteral iron overload: from blood transfusions

- Chronic liver disease

- Aceruloplasminemia

- Congenital atransferrinemia

- NOTE: pts with non-HFE-related iron overload w/elevated HIC should also be tx'd w/phlebotomy


For what infections are ppl with hemochromatosis at high risk?

- Vibrio vulnificus: avoid undercooked seafood 

- Listeria, Yersinia, and other siderophilic bacteria (iron-loving) 


Does HFE respond to therapy?

- Yes, improved survival if b4 cirrhosis/diabetes 

- Reversal of fibrosis (not cirrhosis) 

- Improved glycemic control

- Improved cardiac function

- Reduction in portal HTN (in cirrhotics)

- Elimination of HCC risk: if started prior to cirrhosis (once they get cirrhosis, risk of HCC regardless of whether or not iron levels come back down)

- Reduction in skin pigmentation


What HFE symptoms are not reversible?

- Hypogonadism, arthropathy, cirrhosis irreversible

- Cirrhotic patients should be screened for HCC (3-4% incidence per year); HCC is extremely rare in non-cirrhotic HH patients



What is Wilson's disease?

- Auto recessive excessive Cu deposition: don't want to miss this bc you have to catch it early 

- ATPase deficiency (ATP7b gene), leading to: 

1. Low ceruloplasmin 

2. High free copper in plasma (and urine)

3. High copper in liver 

- NOTE: ATPase is a transmembrane transporter of Cu in hepatocytes; reduced or absent expression leads to DEC Cu excretion into bile and inability to incorporate Cu into ceruloplasmin


What are the complications in Wilson's disease?

- LIVER: chronic hepatitis, cirrhosis, acute liver failure

- BRAIN: basal ganglia, psychiatric 

- KIDNEYS: proximal tubular disease 

- BLOOD: hemolytic anemia 

- NOTE: progressive fatal neurological disease associated with liver cirrhosis

1. Most are <40, but not all young: <40, hemolytic anemia, and liver failure -> think about WILSON’s


What is the normal metabolism of copper?

- Cu absorbed in duodenum and proximal small intestine

- Avid uptake by liver where it is used for metabolic needs

- Majority of excess Cu excreted into bile, and the rest is released into the circulation bound to ceruloplasmin


What are the clinical features of Wilson's?

- LIVER DISEASE (presents earlier in life): wide spectrum -> abnormal LFTs, cirrhosis, acute liver failure

- NEURO DISEASE: Parkinson-like symptoms -> tremor, dysarthria, dystonia, lack of motor coordination, spasticity, dysphagia 

- PSYCH DISEASE: can sometimes affect adherence

- Other organ involvement: cardiomyopathy, pancreatitis, osteoporosis, arthritis, nephrolithiasis


What is this?

Kayser-Fleischer ring: copper deposit in Descemet's membrane of cornea 

- May be absent in isolated hepatic Wilson's: 40-60%

- Also seen in PBC, PSC, other cholestatic disease

- Often disappears with treatment

- Present in 95% of pts with neurological disease

1. Can sometimes see this with naked eye: send to ophthalmologist 


How does Wilson's present with fulminant liver failure? Labs? Tx?

- Acute presentation of a chronic disease: liver failure with encephalopathy and coagulopathy 

- Hemolytic anemia: Coomb's negative

- LABS: low serum alk phos (ALP/Bil < 2)

1. AST/ALT < 2000

- TX: only tx is liver transplant 

- Should be a gradual process, but may not present that way 


When should you suspect Wilson's?

- Any patient < 40 yrs with elevated AST/ALT

1. Takes awhile for the copper to build up

- Neuropsychiatric disease with liver disease

- Any young patient with liver failure

- Presentation at age < 5 yr or > 40 yr is unusual but possible



How do you diagnose Wilson's?

- SERUM CERULOPLASMIN (normal 20-50mg/dl): 95% of these pts have low ceruloplasmin

1. Can be low in pts with decompensated liver disease of any etiology

2. Levels  highly suggest Wilson's

- SERUM FREE COPPER: >25 µgm/dl is typical of Wilson's; mild INC in o/cholestatic liver diseases 

- 24-HR URINE COPPER: >100 microg/24 hrs

- LIVER COPPER CONC: >250 ugm/g; false negative in advanced liver disease w/severe fibrosis 

- GENETIC TESTING: only feasible w/index case (family member) b/c multiple genes and polymorphisms of normal gene 


What is the treatment for Wilson's?

- MEDICAL: chelating agents -> Penicillamine, Trientene, Tetrathiomolybdate, and Zinc

1. Trientene + Zinc is Rx of choice

- Liver transplantation when the liver is too sick 



What is alpha-1 anti-trypsin?

- Protein produced by the liver that neutralizes neutrophil elastase activity

1. Neutrophil elastase is a proteolytic enzyme, released by macros and neutros, and plays a role in host immune defense

- Proper secretion from liver essential for normal serum levels

- NOTE: 2% of Caucasian blood donors have MZ 



What is the alpha-1 AT phenotype?

- SERPINA1 gene (chrom 14): molecule classified as M, S, or Z based on mobility on isoelectric focusing 

- Each person has two alleles (one from e/parent) 

Z defective (ZZ, MZ, SZ) can't be secreted by liver, leading to: 

1. Low alpha 1 AT levels in serum and lung, but

2. Excess in liver: 

- S not clinically important: MS probably normal variant 


What are the manifestations of ZZ?

- LUNG: uncontrolled elastase activity, early emphysema

- LIVER: accumulation, liver injury, neonatal jaundice

- Some pts may have lung AND liver injury, while others may have only one organ w/significant injury

- ZZ: not an equal opportunity disease -> may affect different organs to different degrees 


When should you suspect AAT?

- Cirrhosis of undetermined etiology

- Emphysema with liver disease

- Early emphysema, esp. in non-smokers


How is AAT diagnosed?

- Disease phenotype -> ZZ

- Liver biopsy showing alpha 1 AT granules

1. Diastase resistant PAS positive granules in attached image (red arrows)

- Not a deficiency, but an excess in the liver


How is AAT treated?

- Stop smoking

- Replacement α AT via IV infusion

1. Useful for emphysema

2. Not useful for liver disease

- Treat complications of cirrhosis, i.e., with liver transplantation


Hemochromatosis, Wilson's, AAT: cause, screening, diagnosis, and liver disease chart

- Alpha-1: blood test usually; don’t need to biopsy everyone

- Wilson’s the one that can present as an acute hepatitis: fulminant failure 


What is the risk of HCC in Hemochromatosis, Wilson's, AAT (image)?


What is the impact of liver transplant in Hemochromatosis, Wilson's, AAT?

- HEMOCHROMATOSIS: disease can theoretically recur (clinically rare)

1. No impact on extrahepatic sites (cardiac)

- WILSON's: transplant cures disease 

1. Neuro disease may improve 

- AAT DEFICIENCY: transplant cures hepatic disease 

1. Emphysema irreversible 


What is NAFLD?

- Acquired liver disease in kids/adults: most comm liver disease in US 

- INC w/epidemic of obesity in US 

- Macrovesicular hepatic steatosis

- Ethanol < 20 gm per day: <2 drinks per day

1. Diagnosis of exclusion 


What are the 2 conditions within NAFLD?

- Steatosis 

- Non-alcoholic steatohepatitis (NASH): more serious than steatosis bc fatty liver + inflammation 


What is the epi of NAFLD?

- 20-30% of adults and 10% of kids: these #'s are much higher than for ALD or Hep C 

1. NEXT EPIDEMIC for liver disease 

- "Normal vs. Obese:" can have obese pts w/o these, and thin pts with fatty liver 

1. Fatty liver: 10-15% or normal, 70-80% obese 

2. NASH: 3% of normal, 15-20% of obese

- Associated conditions: obesity, T2D, metabolic syndrome (HTN, diabetes, high BMI), sleep apnea, hyperlipidemia,

- RACE/ETHNICITY: Mexican-Americans, Native Americans highest; AA lowest 

- GENDER: about 50:50

- Familial component: dietary habits, genetics


Pediatric NAFLD?

- Leading cause of pediatric liver disease: 10% of kids 

- Can even have fibrosis and cirrhosis 


What are some other causes of NAFLD?

- Nutritional abnormalities: TPN, starvation/re-feed

- Metabolic diseases: abetalipoproteinemia 

- Occupational chemical exposure 

- Drugs: Tamoxifen, CCS, Amiodarone, MTX, HIV tx

- Surgery: with rapid, excessive weight loss -> jejunoileal bypass in the past (not so much with gastric bypass)


What is the natural history of NAFLD?

- Fatty Liver: limited progression

- NASH: 30-40% with advanced fibrosis and 10-15% with cirrhosis

- NASH-induced cirrhosis is an increasing cause of HCC


How does fat mobilization affect NAFLD?

- Normally, TG's incorporated into chylomicrons

1. Travel via lymphatics to peripheral fat

2. Hydrolyzed to free fatty acids (FFA's)

- Stored in the liver, and oxidized by mitochondria: TG/cholesterol formation

- Steatosis is a result of disturbed balance -> more lipogenesis/INC FFA

- KEYS: a) liver making fat (lipogenesis), b) INC FFA from periphery to liver 

1. INC FFA => fatty liver and INC oxidative stress (INC free radicals, direct liver injury)


How do insulin resistance and obesity contribute to NAFLD?

- INSULIN RESISTANCE: insulin promotes uptake of glu, glycogen storage, and INH lipolysis 

1. INC levels of insulin = INC lipogenesis, and INC FFA (via adipose tissue lipolysis)

2. INC mito FA oxidation, leading to free radical formation and damage 

3. INC circulating insulin shifts FFA to the liver and INC lipogenesis -> oxidative stress/injury 

- OBESITY: INC synthesis of FFA 

1. DEC in oxidation of FFA 


What is the two-hit hypothesis for NAFLD?


1. Hepatic fat accumulation 

2. Oxidative stress via lipid peroxidation of free radicals 

- Fatty liver + inflammation and oxidative stress (just like in ALD)


What are some concomitant liver diseases that can exacerbate NASH?

- Hep C 

- Hemochromatosis 

- AAT deficiency

- Alcohol: child with NASH who grows up and becomes alcoholic can have both 


What are the clinical features of NAFLD?

- Most have no symptoms or signs of chronic liver disease, except: 

1. Fatigue, a non-specific symptoms


What might you look for in the PE of a pt w/suspected NAFLD?

- Obesity: 30-100%  of patients

- Hepatomegaly: up to 50%

- Spider angiomata: red arterioles that come to skin, and have branches that look like spider (image attached)

- Palmer erythema: often spider angiomata in palms of hands


Labs in pts with NAFLD?

- In patients with NASH: 50-90% w/elevated LFT's

1. AST, ALT: moderately high; up to 4x normal; unlike ALD, AST is rarely 2x ALT

2. Alk phos: up to 2x normal

- Not a perfect test -> can be dx'd w/normal liver enzymes 

- Pt. with normal liver enzymes, but platelet count of 88,000 (low) -> underlying fatty liver (think about CIRRHOSIS): EXAM


What might you see on US of pt with NAFLD?

- Homogeneously fatty, infiltrated liver

- INC echogenicity throughout

- CAUTION: “fatty” appearance on US or CT does not make a diagnosis


What might you see on CT/MRI of someone with NAFLD?

- Different density of liver and spleen, which should be the same -> different due to fatty infiltration 

- CAUTION: “fatty” appearance on US or CT does not make a diagnosis


Can a liver biopsy help dx NAFLD?

- Controversial, but helps to exclude other causes

- Liver biopsy is only definitive way to dx NASH -> helps to stage the disease


What do you see here?


1. LEFT: predominately macrovesicular steatosis + Mallory hyaline hepatocyte ballooning

2. RIGHT: perivenular and perisinusoidal fibrosis with “chicken wire appearance”

- Usually neutrophilic infiltration more common with alcohol, but can be in both 


What is the tx for NAFLD?

- Weight reduction! 

1. Weight reduction of 10% helpful

- If diabetic, optimize control

- If hyperlipidemic, treat this, particularly due to the increased cardiac risks

- No magic medication 

- Many of these pts will die of complications of heart disease

-Interestingly, coffee helps reduce risk of complications of liver disease in people with fatty liver (and viral hepatitis) 


Sx tx for NAFLD?

- Surgery may have a role in properly selected pts

1. Can help pts with diabetes, liver inflam, and fibrosis

- Bariatric surgery may help people with NASH whose BMI is >35

- Gastric banding associated with improvement in inflammation and even fibrosis

- Fibrosis (cirrhosis) can also improve with weight and diabetes control

- INC operative risks, but can be worth it 


Liver transplant for NAFLD?

- Sometimes -> NASH is felt to be a major cause of cryptogenic (idiopathic) cirrhosis

- Hepatitis C + NASH are increasing causes of cirrhosis and HCC

- May be difficult for pathologist to determine cause of hepatitis/HCC if pt. stopped drinking/overeating 10-15 years before presenting with these/dying 


What are the liver complications that people die from?

- Esophageal varices 

- Renal failure 

- HCC: used to be a novelty, but more common now

- Ascites: bacterial peritonitis

- Hepatic encephalopathy: aspiration pneumo from saliva, or acute liver failure w/death in days (Hep B)

- Have to think about, and find, these things 


In what contexts can you see hepatic encephalopathy?

- Acute liver failure 

- Portosystemic shunt w/o liver failure 

- Chronic liver failure: 

1. Precipitated 

2. Spontaneous 

3. Recurrent 


What are the proposed mechs of hepatic encephalopathy?

- AMMONIA, nitrogenous wastes from portal circulation -> brain shouldn’t be seeing these

- INC intracellular GLUTAMINE

- Astrocyte swelling, and cerebral edema

- Inflammatory cytokines alter BBB

- INC benzodiazepine receptors, INC neuro-steroids, INC GABA receptor activity

- MANGANESE: neurotoxin that deposits in basal ganglia

- More sensitive to things like Valium 

- Can cause brain injury 


Acute hepatic encephalopathy features?

Acute liver failure: coagulopathy and altered mental status within 2 wks of jaundice

- Alteration of BBB, and acute cerebral edema (see attached image) 

1. Cerebral edema can result in cerebral herniation (into foramen magnum): brain swells so much, fluid is pressed out of where it should be (brain taking up all the space)

- Major COD from acute liver injury, incl. Tylenol OD

- FRONT IMAGE: pt elevated in bed due to risk of cerebral edema

1. Tube to give meds to help her survive  


Chronic hepatic encephalopathy onset?

- Often slow and subtle onset

- Often noticed by family members

- Milder symptoms frequently missed by coworkers or physicians until quite severe



What are the stages of hepatic encephalopathy?

- Become less and less responsive:

1. Grade I: irritability, insomnia, agitation

2. Grade II: indifferent, personality change, short-term memory impairment, mildly disoriented about time or place

3. Grade III: drowsy but arousable, significantly confused and disoriented to time and place

4. Grade IV:  coma 

- NOTE: ppl that have known them for yrs notice these changes 


What might you see on PE of someone with HE?

- NEURO EXAM: alert, orientation to time place, date, president, family member birthdates, etc.

1. Sometimes they are just a little off, like one year off birthdate 

- ASTERIXIS: hyperextend wrists and observe for repetitive movement (“flap”), inability to perform sustained grip of the hand

- MYOCLONUS: with hyperextension of the ankles

- Absence of sensory, motor or cerebellar deficit to suggest another etiology for altered mentation 

- Absence of autonomic hyperactivity, tachycardia, hypertension -> to suggest other etiologies

1. Tachycardia, HTN: worried about cerebral edema


Is chronic hepatic encephalopathy reversible?

- Generally, yes, with treatment, but may have mild DEC in mentation, calculations

- If long-standing, permanent brain damage can occur 

- RARELY results in irreversible dementia: this can keep people off the transplant list 

- Rarely permanent mvmt disorders 



What is the tx for HE?

- Treat precipitating conditions:

1. Hypovolemia: correct causes, i.e., diuretics, meds that caused excessive diarrhea

2. Hypokalemia: diuretics 

3. GI bleeding: blood in GI tract is high protein load, INC nitrogenous waste: come in, they’re talking to you, then when admitted, they aren’t talking back bc blood being absorbed

4. Prescribed meds, sedatives, substance abuse: too good of a job; paradoxical rxn, worsening the irritation (IATROGENIC)

5. Infection: evaluate for common systemic infections like meningitis (lumbar puncture)

6. Exclude intracranial hemorrhage: falls with thrombocytopenia, coagulopathy (high INR)

a. If PLT count 39,000, you can fall, hit head, and get intracranial hemorrhage, and probably won't remember this 


How is lactulose used to treat HE?

- Poorly absorbable sugar

- Cathartic 

- DEC intestinal pH

- DEC glutamine absorption

- Reduces synthesis and absorption of NH3


How is zinc sulfate used to treat HE?

- Zinc is a cofactor in NH3 metabolism

- Zinc deficiency is common in liver disease

- Correction of Zinc deficiency is part of the tx of encephalopathy


What AB is given to tx HE? Why?

- Rifaxamin: 

1. Alters intestinal flora, changing chemistry of GI tract

2. DEC NH3

3. DEC intestinal mucosal glutaminase

4. DEC coliform bacteria that produce urease and convert urea to NH3 


What nutrition is important in the tx of HE?

- Nutrition improves the underlying liver disease

- Malnutrition is common in liver pts

1. Skeletal muscle metabolizes NH3

- Protein restriction NOT helpful: malnourished already, so protein restricting them not good 

1. Not eating well to start out with 

- High vegetable proteins with INC branched-chain amino acids advised


What are the chronic neuropsych complications of cirrhosis?

- DEC functional capacity despite medical therapy

- Dementia

- Parkinson’s like syndrome

- Cerebral edema

- NOTE: can have these complications with chronic encephalopathy, but they are just not that common 


What is the concern with porto-caval shunts?

- Surgical porto-caval shunts and transjugular porto-systemic shunts (TIPS) can cause hepatic encephalopathy 

- Help DEC pressure and prevent bleeding, but can have portal blood going into systemic chronically, and cause complications 


What do you need to rule out b4 concluding neuropsych cxs are from cirrhosis?

- Exclude/treat depression

- Neurological evaluation to exclude other forms of dementia

- Neuropsychiatric testing with optimization of HE treatment

- Re-testing after Flumazenil

- Assess candidacy for liver transplantation 


What are the symptoms of hepatic dementia?

- Fluctuating symptoms

- Attention deficit

- DYSARTHRIA: difficult or unclear articulation of speech that is otherwise linguistically normal

- APRAXIA: inability to carry out learned purposeful movements


What is hepatocerebral degeneration?

- Risk with recurrent, severe HE: uncommon, but can happen

- Neuropsychiatric disorders

- Movement disorders, myoclonus

- Cerebellar symptoms

- Myelopathy


What does this show?

- INC intensity in globus pallidus with T1 weighted MRI in cirrhotic pt

- Associated with severity of neurological findings

- Associated with worsened NH3 levels

- NOTE: most of these resolve when liver replaced


What are the neuropathological findings with cirrhotic hepatocerebral degeneration?

- Patchy cortical neuronal loss

- Alzheimer type II astrocytes

- Neuronal drop out in the cerebellum and basal ganglia

- IMAGE: globus Pallidus with myelin degeneration*, axonal spheroids


Is cirrhotic hepatocerebral degeneration reversible?

- Improvement with liver transplantation has been described in approximately three months

- Improvement in basal ganglia abnormalities on MRI



What are these?

- Alzheimer T2 astrocytes: seen in metabolic encephalopathy

- Large, round, (sometimes lobulated) vesicular nuclei with scanty chromatin and prominent nucleolus

- Occasionally may contain glycogen inclusions

- IMAGE: autopsy of pt with cirrhosis


What are the renal cxs with liver disease?

- Hepatorenal Syndrome

- IgA Nephropathy

- Membranoproliferative glomerulonephritis

- Membranous glomerulonephritis 


What is hepatorenal syndrome?

- One of most feared complications of acute liver failure or cirrhosis 

- Liver failure causes renal arterial vasoconstriction and renal failure -> NOT associated with underlying renal parenchymal abnormality

1. Liver telling kidneys to vasoconstriction to point of renal failure -> cirrhosis and ascites 

- Generally reversed with correction of liver failure, such as with transplantation

- Serum creatinine > 1.5 mg/dL

1. No improvement (DEC < 1.5) with holding diuretics and volume replacement for 2 days

- IV Albumin 1gm/Kg: up to 100 gm/day 

- Absence of shock; no recent nephrotoxic drugs

- No underlying renal disease: >500 mg protein per day, >50 RBCs/hpf or abnormal renal ultrasound


How is hepatorenal syndrome dx'd?

- Exclusion of other etiologies

- Lack of return of renal function with intravascular volume repletion


What are the 2 types of hepatorenal syndrome?

- Type I: rapid worsening: creatinine >2.5 mg/dL or decrease in CrCl <20 ml/min within 2 wks

- Type II: slow progression, often with worsening liver disease

1. This is what we generally see

2. MELD score: Cr going up is a poor sign of liver function 

- NOTE: normal CrCl b/t 90 and 130 


What is the mechanism of hepatorenal syndrome?

- Peripheral artery vasodilation

- Stimulation of renal SYM nervous system, and RAS

- Cardiac dysfunction, impaired contractility

- Cytokines and vasoactive mediators, incl. TNF-ɑ, NO, endothelin, endotoxin 


What is the tx for hepatorenal syndrome?

- IV volume repletion

- Tx underlying infection, i.e., spontaneous bacterial peritonitis

- Avoiding meds that can worsen renal perfusion (NSAIDs)

- Avoid IV contrast, which results in renal injury

- Optimize renal perfusion

- Liver transplantation: hemodialysis until liver transplantation


What is IgA nephropathy?

- Liver disease is MCC of 2o IgA Nephropathy

- INC deposition of IgA, C3, and o/immunoglobulins in 35-90% of cirrhosis patient

- DEC hepatic clearance of IgA with cirrhosis and portal HTN: with collateral blood flow around the liver

- Pediatricians see this more often 


What is membranoproliferative glomerulonephritis?

- Associated with chronic Hepatitis C

- Cryoglobulinemia: abnormal protein in the blood that precipitates with cold temperatures

1. Immune complex formation with chronic Hep C: Ag-Ab complexes deposit in kidney 

- When you see Hep C, don’t just think about the liver

- These people can be on dialysis, even if liver biopsy just shows mild fibrosis


What is this?

Cryoglobulinemia: proteins that precipitate when tube of blood is chilled

- Vasculitis

- Happens in parts of body that are the coolest: feet and lower legs, where circulation is not as efficient 

- Rarely in hands, but possible


What is the role of INF in renal dysfunction?

- INF in Hep C did not help with the renal failure

- Hep C can be cured, even w/immunosuppression in the future

1. Can catch it again because we don’t have neutralizing Ab’s, but this is NOT common 


What is membranous glomerulonephritis associated with?

- Associated with: 

1. Hep C

2. Hep B