Liver Cirrhosis, ddx, and more

Had to do some reading for a patient presenting with abdo pain and transaminitis nyd. I compiled some notes from Lauras's teaching session, lectures, and the website below. The website is a good reference guide for commonly used liver function tests.

http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hepatology/guide-to-common-liver-tests/#top


Contents:

• Liver Cirrhosis ddx
• Acute Hepatitis ddx 
• Liver Enzyme Interpretation
• Approach to Bilirubin and Jaundice
• Liver tests in specific liver disorders (summary of website)
• Cirrhosis (Laura's teaching session and lecture)

LIVER CIRRHOSIS

Causes		Tests
		Enzymes: AST, ALP, ALT, GTTP, LDH LFTs: bilirubin, albumin, INR, PTT, glucose Other: plt, cbc (anemia)
Toxic	EtOH	AST/ALT>2 + GGTP; GGTP used to monitor alcohol abstinence Dx with
Viral	Hep B Hep C/D	HBsAg, Anti-HBs, Anti-HBc, HBeAg, Anti-HBe Anti-HCV, HCV RNA
Cholestasis	PBC PSC Bile duct obstruction	Inc in ALP Elevated ALP, pos anti-mito ab (AMA), MRCP, liver bx MRCP, liver biopsy U/S, ERCP, MRCP
Autoimmune	Autoimmune hepatitis PSC (see above)	ANA, ESR/CRP, IgG levels, Anti-SM antibody(SMA), anti-mito ab (AMA), liver-kidney microsomal antibody (LKM), anti-liver cytosol type 1 Ab
Genetic	Wilson’s Hemochromatosis A1AT def	Ceruplasmin, serum copper, 24hr urine copper, KF rings, biopsy Iron indices: elev serum iron, ferritin, and TSat, decrease IBC and transferrin-R; genotype, biopsy Alpha 1 AT levels, liver biopsy
Metabolic	Non-Alcoholic Fatty Liver Disease (NAFLD)	Inc AST&ALT; liver imaging U/S, metabolic testing, liver biopsy

ACUTE HEPATITIS

Causes	Tests
Viral ·         Hep A ·         Hep B	Anti-HAV IgM, Anti-HAV IgM (for past infection) HBsAg, Anti-HBs, Anti-HBc, HBeAg, Anti-HBe
Autoimmune hepatitis	ANA, IgG, Anti-Sm Ab, AMA, LKM, Anti-liver cytosol type 1 Ab
Drugs: acetominophen	History, Tox screen
Vascular ·         Bud-Chiari ·         CHF ·         Constrictive Pericarditis ·         Sinusoidal venous thrombosis	Abdo U/S w/ Doppler study
Biliary obstruction	U/S, ERCP, MRCP

Danger signs:

·         Liver function tests: INR, bilirubin, albumin, glucose

·         Liver enzymes: AST, ALT, ALP, GGTP, LDH

·         Signs: Confusion, jaundice, ascites, bleeding (GI)

Liver enzymes Interpretation

·         Normal

o   AST <40IU/ml

o   ALT <35IU/ml

o   ALP <130IU/ml

·         Classify

o   Hepatocellular cause – AST and ALT >500U/L higher than ALP level <3xULN

o   Cholestatic cause – ALP (>3xULN) higher than AST ALT (elevated <200 or near normal)

o   Infiltrative – elevation in ALP with near normal AST, ALT

§  Often require imaging studies: US, CT, MRI

§  Liver biopsy

·         Very High AST/ALT (>1000):

o   Viral: HAV, HBV

o   Drugs

o   Autoimmune hepatitis

o   Vascular liver disease

o   biliary Obstruction

·         ALT 200-500

o   Alcohol liver disease

o   Viral hepatitis

o   Wilson’s

o   Hemochromotosis

o   NASH

·         Moderately high AST and ALT with sig liver synthetic dysfunction (INR, BILI, alb):

o   Cirrhosis

o   liver failure

·         GGTP points to liver related pathology in context of increased AST/ALT

Approach to Bilirubin and Jaundice

·         Pre-hepatic, hepatic, post-hepatic

·         Increased total bilirubin >90% unconjugated

o   Common:

§  Gilbert syndrome – genetic, no associated with liver disease

§  Hemolysis

·         Anemia, and elevated retic count, haptoglobin, LDH, normal liver enzymes

o   Approach:

§  Not liver related = increased bili production

·         Hemolytic anemias

·         Hemolysis from drugs – sulfa, nitrofurantoin, ribavirin

·         Hematomas

§  Liver Related

·         Decrease uptake: Drugs, CHF

·         Decreased conjugation: Gilbert syndrome (decreased glucuronyl tranferase; usually asymptomatic), Crigler-Najjer Syndrome, Drugs (estrogen)

·         Increase Conjugated bilirubin (unconjugated elevated or normal)

o   Liver disease

§  Elevated liver enzymes

§  Bilirubin in urine

o   Approach

§  Hepatocellular Damage: Viral hepatitis, alcohol liver disease, Drugs (acetaminophen, INH, statins), Sepsis/infection, autoimmune,

§  Intrahepatic cholestasis: infiltration (Ca, infections, sarcoid), drugs- OCP, Amox/clav

§  Biliary obstruction: gallstones, bile duct carcinoma, sclerosing cholangitis, pancreatitis, extrahepatic tumours

·         Hx:

o   HPI: onset, Urine(dark), stool (pale in biliary obstruction, melena, BRBPR), infective symtoms (viral), pruritis, steatorrhea, aobdo pain (PSC, PBC), nausea, vomiting, w/l, easy brusing, bleedin GI

o   ROS: C/S, abdo pain, autoimmune (joint pain, swelling, itching, dry eyes, mouth), psych ( wilsons), skin discoloration, missed menses

o   PMHx: hepatobiliary dx, hemolytic disease, infiltrative disorders “(sarcoidosis, lymphoma, fungus, tb), HIV, gall bladder surgery

o   Medications

o   SHx/FHx: alcohol intake, etc

·         PE:

o   Scleral icterus: seen with bili 34-43, KF rings, general wasting, jaundice

o   Mental status: asterixis

o   Skin: jaundice, palmar erythema, needle tracks, vascular spider, excoriations, xanthomas

§  Hyperpigmentation (Fe overload)

§  Bleeding: ecchymoses, petechiae, purpura

o   Abo, liver, spleen, ascites, rectum

Investigations in Specific liver diseases

·         Acute Alcohol hepatitis

·         Hepatocellular pattern:

·         AST 100-200, ALT may be normal; AST:ALT >2:1

·         Indicators of severity  - bili and PT elevation

                                                   i.      MDF score >32àincreased risk of death

·         Viral Hepatitis – hepatocellular pattern of injury

·         Hep A

                                                   i.      Acute, self-limiting dx

                                                 ii.      Dx:

1.       Anti-HAV IgM – positive from onset to 3-6 months; suggest acute infection

2.       Anti-HAV IgG – develop later; past infection or post-vaccination

·         Hep B

                                                   i.      Commonly acute but sometimes chronic

                                                 ii.      Acute Hep B

1.       HbsAG –pos or neg (presenting late)

2.       Anti HBc -pos

3.       Anti-HBs –neg

                                                iii.      Chronic Hep B

1.       Persistence of HBsAg >6months

2.       Anti-HBc IgG - pos

3.       Anti HBs – neg

4.       HBeAg – positive in active viral replication and sig liver inj

5.       Anti-HBe – develops with HBeAg resolution; associated with lower levels of viral replication and less hepatic inflammation

                                               iv.      Resolved Hep B

1.       HBsAg – neg

2.       Anti-HBc –pos

3.       Anti-HBs –pos

                                                 v.      Post immunization to HepB

1.       HBsAg – neg

2.       Anti-HBc – neg

3.       Anti-HBs – Pos

                                               vi.      HBV DNA levels  help in predicting progression to cirrhosis in chronic Hep B, and need for treatment in HBeAG neg patients

                                              vii.      Certain HBV genotypes ass with early HBeAG seroconversion, less progression to cirrhosis and HCC, and response to treatment

·         Hep C

                                                   i.      Infrequently diagnosed in acute phase due to mild symptoms

1.       Testing for possible acute infection: HCV RNA PCR

2.       Suspect chronic HCV: Anti-HCV EIA

                                                 ii.      HCV genotype: treatment determination

                                                iii.      IL28B testing in patient DNA in genotype 1 for treatment consideration

1.       Treatment response and duration

·         Iron Overload

·         Hereditary hemochromatosis – in northern European descent;

                                                   i.      Serum ferritin, iron, IBC, transferrin saturation levels

                                                 ii.      T sat<45% +normal serum ferritin à r/o iron overload

                                                iii.      T sat >45 and/or serum ferritin above normal à further investigation

                                               iv.      Limitation

1.       Any acute hepatocyte injury will falsely raise iron, transferrin, and ferritin levels

2.       Ie in context of elevated ast/alt in acute viral hepatitis or hepatic necrosis. Iron studies cannot be interpreted in the face of major elevation of transaminase levels

3.       Normal iron studies do not preclude future iron overload esp if pt is young and has not had enough time to accumulate iron

                                                 v.      Genetics: Gene is HFE with two sites involved with missense mutation: C282Y and H63D

1.       Diagnostic: homozygosity for C282Y and compound heterozygosity for C282Y/H63D OR liver biopsy

2.       Premenopausal with HH don’t often have iron overload yet

3.       Incomplete penetrance in homozygotes ie may not show disease with overload despite having the genotype

4.       Prognosis: liver biopsy for extent of cirrhosis

                                               vi.      There is normal increase in hepatic iron in normal individuals

·         Copper Test- Wilson disease

·         Pathological copper deposition àliver injury, cirrhosis, death

                                                   i.      Also accumulates in basal gangli

·         Fatal before age 40 untreated

·         Diagnosis: low ceruloplasmin level

                                                   i.      May be low due to terminally failing liver or other genetic condition without liver disease

                                                 ii.      Other test: 24hr urine copper levels, slit lamp examination looking for KF rings

                                                iii.      1^st line ix: low ceruloplasmin, raise serum free copper levels, high urine copper and presence of KF rings

                                               iv.      2^nd line ix: biopsy liver, genotype

·         Autoimmune Liver disease

·         Most common: autoimmune chronic hepatitis and PBC

·         Predominantly women

·         Autoimmune hepatitis

                                                   i.      Tests:

1.       High serum aminotranferases compared to ALP

2.       Anti-SM ab positive

3.       ANA

4.       Some cases positive liver-kidney microsomal antibody positive

5.       Anti-liver cytosol type 1 liver ab

6.       Elevated IgG

7.       2^nd: liver biopsy

·         PBC:

                                                   i.      cholestatic: auto immune disease involving the intrahepatic small bile duct

                                                 ii.      Tests

1.       high ALP compared to AST/ALT

2.       Anti-sm ab usually neg

3.       Anti-mito ab (AMA) positive – high sensitivity and specificity

4.       Liver-kidney microsomal ab negative

5.       r/o bile duct obstruction with U/S

6.       diagnostic: elevated alp and pos AMA ab

·         Non-alcoholic Fatty Liver disease

·         Accumulation of fat in the lvier in the absence of conditions that cause secondary fat accumulation such as alcoholic hepatitis, medication, metabolic disorders or viral hepatitis

·         Profile: non alcoholic, usually obese, high BMI

·         Diagnosis: elevated ast/alt <1 ratio, liver imaging, biopsy, CK18 to predict liver injury, alcohol intake history to r/o

·         NASH: evidence of hepatocellular injury/inflammation in addition to fat accumulation; diagnosed only on liver biopsy

Cirrhosis

·         Physical findings: spinder angiomata, palmar erythema, clubbing, terry’s nails, hyerptrophic osteoarthropathy, dupuytren’s cotnractures, gynecomastia, testicular atrophy, fetor hepaticus, hepatomegaly, splenomegaly, ascites, caput medusa, asterixis, venous hum, jaundice

·         Lab findings:

                           i.      Moderate AST ALT elevation or normal, mild ALP elevation, GGT

                         ii.      Bili increase with decompensation

                        iii.      Alb as synthetic function decreases

                       iv.      INR increase

                         v.      Decrease Na conc in cirrhosis + ascites due to high ADH

                       vi.      Anemia

1.       GI losses

2.       Folate deficiency

3.       EtOH related

4.       Hypersplenism

5.       Anemia of chronic disease

6.       Hemolysis

                      vii.      Thrombocytopenia: portal HTN, congestive splenomegaly

                    viii.      Leukopenia

                       ix.      Neutropenia- hyperplenism

                         x.      Elvated Ig

                       xi.      Worsening coagulopathy

1.       DIC, fibrinolysis, VitK def

2.       Dysfibrinogenemia

3.       Thrombocytopenia

·         Order of synthetic dysfunction

                           i.      Decrease in plt, increase in INR, decrease albumin (ascites), increase bilirubin(encephalopathy)

·         NON invasive tests for liver Cirrhosis

                           i.      Serological markers

1.       Direct: associated with deposition of matrix eg P3NP – procollagen type III amino-terminal peptide; reflect degree of fibrosis in chronic liver dx

                         ii.      Hepatic elastography: U/s based: fibroscan; correlate with liver stiffness; also MRI based elastography

                        iii.      Fibrotest: age, gender, GGT, bili, alpha 2 macroglobulin, apolipoprotein A1, haptoglobin

                       iv.      Imaging

1.       U/S for Ascites, HCC, hepatic vein thrombosis, portal thrombosis

·         Complications

                           i.      Ascites, SBP, hepatorenal syndrome, variceal hemorrhage, hepatopulmonary syndrome, hepatic hydrothorax, loss of liver synthetic functions, Portal HTN, hepatic encephalopathy, HCC, portal vein thrombosis

                         ii.      Ascites

1.       Causes

a.       Portal HTN: SAAG>11; liver cirrhosis, acute hepatitis, CHF, bud-chiari

b.      Non-portal HTN: SAAG<11; peritoneal carcinomatosis, TB, pancreatic ascites, biliary ascites, chylous ascites, nephrotic syndrome, bowel obstruction/infarct, serositis

2.       paracentesis: bacterial culture, Cell count (PMN>250, WBC>500 with 75%PMNs), glucose, protein, albumin, cytology (malignancy)

3.       Rx:

a.       Na restrict <2g/day, fluid restrict

b.      Lasix:spironolactone in 20:50 ratio increase as tolerated to max 160:400

c.       Therapeutic paracentesis

d.      Indwelling cath if palliative – high risk for infection

e.      TIP- endstage only, comp of hepatic encephalopathy 40-50%

                        iii.      SBP:

1.       Sx: asymptomatic w/ mild lab abn OR fever, abdo pain, abdo tenderness, altered mental status

2.       Dx paracentesis: bacterial culture, Cell count (PMN>250, WBC>500 with 75%PMNs), glucose, protein, alb

3.       Decreases prognosis

4.       Lifetime Prophylaxis after 1st SBP: ciprofloxacin 500mg PO daily or Norfloxacin 44mg po daily lifetime

5.       Rx: Ceftriaxone 2 g IV q 24hrs, albumin 1.5g/kg x1d OR 1g/kgx3d

                       iv.      Variceal Bleeding

1.       Symptoms: hematemesis, melena/hematochezia with brisk bleed

2.       Signs: melena, encephalopathy, ascites, hematochezia, splenomegaly

3.       Rx

a.       ABCs, large bore IVs x2, group,screen,Xmatch

b.      CBC stat – transfuse <70 or +++bleed

c.       Hold: ASA, NSAIDS, anticoags

d.      Pantoloc 40mg IV BID OR 80mg IV bolus then 8mg qhr

e.      Octreotide 100mcg IV bolus, then 50mcg/hr

f.        SBP proph – ceftriaxone 1g IV q24hr

g.       Correct coagulopathy

4.       Screening OGD q1-2yrs and at diagnosis

5.       Prophylaxis: Nadolol 10-160mg OD (HR<55, 25% reduction in HR)

                         v.      Hepatic encephalopathy (clinical dx)

1.       Fully reversibility of symptoms

a.       state of consciousness (change in sleep, slow response, lethargy, disorientation, somnolence, confusion)

b.      intellectual function (loss of orientation, attention, computation)

c.       personality-behaviours (euphorias, depression, irritability, anxiety)

d.      neuromuscular abnormalities (tremor, asterixis, incoordination)

2.       Triggers: drugs (opioids), infection (SBP), liver failure, GI bleed, constipation, large protein meal

3.       Rx:

a.       Lactulose 30mg PO q1h until BM, then 30mg q4hr titrate to 3-4 soft BM/day + Rifoximin 550mg po BID

b.      If severe PEG lyte colon cleanse 1-4L over 4 hours

c.       Avoid opioids and benzo

                       vi.      Coagulopathy (deficiency in all factors can occur except F8)

1.       Thrombocytopenia, increase INR/PTT, decrease fibrinogen

2.       Rx – not treat if not bleeding

a.       If bleeding or procedure

                                                                                                   i.      PLT transfusion

                                                                                                 ii.      FFP, Vit K (F2,7,9,10)

1.       FFP indications (PT>3, INR<1.5):

a.       Active bleeding

b.      Anticipated invasive procedure

c.       Massive PRBC transfusion (dilutional coagulopathy)

d.      Congenital Def factors with bleeding/invasive procedures),

e.      emergent warfarin reversal

f.        plasmapheresis for TTP

                                                                                                iii.      Cryoprecipitate – primary indication is hypofibrinoginemia

                                                                                               iv.      Aside: Octaplex (PCC) only used for bleeding on Warfarin

                      vii.      Hepatorenal syndrome

1.       Mechanism: prerenal AKI that does not respond to IV fluids; develops secondary to liver failure, portal HTN, ascites, and intense renal vasoconstriction in response to low EABF

2.       Rx – octreatide (somatostatin anologue causes splanchnic vasoconstriction), midodrine (alpha adrenergic agonist vasopressor), albumin

a.       Liver transplant – resolves HRS

                    viii.      HCC

1.       Screening: abdo U/S q6mo, AFP; liver MRI if positive

·         Child-Pugh Classification: extent and prognosis of liver cirrhosis

                           i.      Bilirubin, albumin, PT, INR, encephalopathy, ascities

·         Rx:

                           i.      treat underlying cause: virus, alcohol, obstruction

                         ii.      minimize complications

1.       HAV/HBV vaccination

2.       Avoid alcohol

3.       Screening endo

4.       U/S surv for HCC

5.       Weight reduction

6.       SBP prophylaxis

                        iii.      Liver transplant consideration