GI E1

CD location and symptoms

Transmural Inflammation of any part of GIT but usually near ileocecal valve (often discontinuous), can lead to fibrosis, strictures/fistula

Is WATERY DIARRHEA (Blood rare), RLQ abedominal pain, low grade fever, malabsorption, weight loss

UC location and symptoms

Mucosal inflammation start at distal rectum and up into colon

Symptoms: BLOODY diarrhea, rectal urgency, feeling of incomplete defecation, weight loss

3 parts of patho for CD/UC (what specific for CD vs UC)?

Antigen exposure: rip epithelial barrier, access of bacterial antigens to APCs (dendritic cells)

T cell activated: APC present antigen to CD4+ and secrete cytokines:

Dendritic cell turn Th10 Cell into Th1 cells (seen more in Crohn's disease): TH1 cells then release IFNy and TNFa to activate macrophage

TH2, reg, and 17 more so UC

TH2 cells recruit lymphocytes and onocytes, or leukocytes, requires integrin adhesion molecule

Mesalamine based therapy aminosalicylates MOA, location where, and effectiveness for UC vs CD?

Metabolized in distal gut to form AZO BOND LINKS To bccteria ONLY

5-ASA is a metabolite that is reponsible for anti inflammation, but not thorugh COX inhibition but rather directly inhibit IL and TNF (exact MOA unknown)

Location: Acts at varying sites in GIT (cna be suppository, enema, delayed release, pH coating)

Effectiveness: More effective in UC than CD (UC for mild to moderate, CD has modest benefit and not great for remission)

Amino salicylates PK? (metab special how?)

Sulfasalazine: metabolized to 5-ASA and sulfapyridine:

Sulfa pyridine is highly lipid soluble and goes through extensive liver metab

Acetylation phenotype DETERMINES ADES for SULFAPYRIDINE

Corticosteroids MOA and use

Anti inflammation

used for acute attacks and pts with moderate to severe disease

40% are responsive, 30-40% have partial repsonse/become dependent and 15-20 just don't respond

6 mercaptopurine prodrug form, MOA, issues/Metab special how?

Purine analog metab that impairs PURINE bio synthesis and inhibit cell proliferation

Can cause pancreatitis, fever, BONE MARROW SUPPRESSION

Polymorphism in TPMT have increased risk of bone marrow suppression

Azathioprine is PRODRUG FROM

6 MPT goes through 3 metabs (Xo -> 6 hioturic, TMPT to 6mmp and HGRT to 6 thioguanine), but main one is TPMT into 6 methyl MPT (however if have low TPMT then more danger)

Giving IM /SC for induction and remission of Crohn's. is unaltered in urine, and quick t1/2.

Immunomodulator for those are have severe IBD and are steroid resistant/dependent

Methotrexate MOA, use in only what? Dosing how?

Folate acid analogue that inhibits DHFR to block DNA synthesis and cause cell death, inhibit T cell activation

USE ONLY IN CROHN'S

IM/SC Dosing

Biologics MOA, use for what, inflixi vs adali, vs certoli?

Binds and nuetralize soluble and membrane bound TNFa, blocks TH1 response (used only for Crohn's)

Inflixi: chimeric mAB that is IV

Adalimumab: human Mab against TNFa that is SC

Certolizumab pegol: humanized peglyated Fab against TNFa that is SC

Janus kinase inhibitors description

PO small moleucle drugs that inhibit transcription of inflammation cytokines, is variably selective (tofacitinib treats UC inhibits JAK1 and JAK3, updactinib treats both UC and Crohns, target Jak)

Only use if failed TNF

Ustekinumab and Risankizumab MOAs

Uste: MAB that targets subunit to IL12 and Il23 to prevent activatino of receptors on lymphocytes

Risan: il23 antag

Vedkolizumab MOA

Used for CD, inhibits leukocyte adhesion and migratino by targeting a4 integrin

Sphingosine-1 phosphate receptor modulators (2) and MOA

Etra and ozanimod are oral S1p recepctor modulators: (S1p for immune cell trafficiking, affect immune cell migration from lymphoid organs to circulatory system then)

IBD description

DiChronic disease with relapsing inflammation amnd ulceratino of intretsine

UC and CD are both multi non instetinal comorbidities associated

Type 1 peripheral arthritis, oral ulcers, inflammatory skin and oculr lesions

Primary sclerosing cholangitis

Osteroporoiss, ankylsogin sponydlyitis

UC classic presentation, how diagnose, and begins where?

BLOODY DIARRHEA, tenesmus, rectal urgency (Can have unexplained weight loss and growth retardation in children)

Diagnose through colonoscopy or sigmoidoscopy (include CBC, CRP, fecal cal protein stool culture CDiff assay)

Always starts in rectuma nd up into colon

5 types of UC and how far up

Proctitis (only rectum)

Proctosigmoiditis (litter higher)

Above is 46% of patients

DISTAL COLITIS/left sided: full left side of colon: 17% of patients

Extensive colitis (next semgnet) and pancolitis (FULL): 37% of patients

Mild vs moderate vs severe UC how many poops abnormal labs? symptoms?

Mild: < 4 stools/day with minimal blood, Normal HR< CRP and ESR, MILD ab pain and tenesmus

Moderate: 4-6 BLOODy stools/day: normalt o minimally elevated HR, CRP and ESR

Mild anemia (Hgb>10), mild-moderate pain tenesmus, NO WEIGHT LOSS

Severe:>6 BLOODY stools/day, >37.8 Celsius, >90bpm HR, Hgb

Low risk for long term complications how for UC?? (Diagnosis age, disease, what kind of coliits, normal what? no cuts how? No extra what?)

Diagnose at >40 years

Mild-moderate disease

Proctitis, proctosigmoiditis, or LEFT sided colitis

NO EXTRA INTESTINAL MANIFESTATION

No fever/weight loss, normal labs, no deep ulcerations

High risk for long term complicatino for UC how? (Age, disease, what kind, drug requriement? hx? labs bad how and infectinos of what)

Age < 40 years at diagnose

Moderate-dsevere disease

EXTENSIVE COLITIS

Glucocorticoid requried for remission

Hx of hospitalization for UC

Deep ulcerations, elevated CRp/ESR

CDiff or CMV infection

Crohn's Disease ileoclitis vs perianal vs colitis vs other presentations for each kind?

Ileocolitis (only ascending colon and ileum), is 50% of patents, ab crampin on lower RIGHT side and Watery diarrhea+weight loss

perianal (25%): Bloody diarrhea+PERIANAL FISTULAS

Colitis (20%): bloody diarrhea, perianal fistulas and abscesses

Other: low grade fever, malabsorption (iron, zinc, folate, b12)

Complications ofr Crohn's idsease and how diagnose?? When do MRI?

Stricture, obstructiona nd fistulas, seen

Diagnose through CT/MRI/US (MRI FOR PATIENTS

CD Mild vs moderate-severe vs severe-fulminant (symptoms, bowel, deficiencies, signs of what? How respond to drugs?)

mild: low risk of progression and surgery: no systemic signs of toxic, normal/slight CRP or FC elevation, limited bowel invovlement, no perianal, no severe lesion, strictures or fistulas

Moderate-severe: Refractory to 1st line treatments for mild-moderate CD, fever/wegith loss, ab pain, N/V

Elevated CRP/FC, anemia or vitamin/mineral def, larger ulcers, bowel inveolement, fistulas, perianal inovleemt

Severe: Continued symptoms ON CORTICOSTOIERDS /biologics

HIgh fever, rebound tenderness, severe mucosal disease, signs of intestinal obstruction/abscess

Risk factors for long term CD complication? (Age use, disease level, use, hx, response to cortico?

Diagnose at

Pre biologic vs biologic era drugs 3+2

Pre: 5-ASA (NOT EFFECTIVE FOR CD), corticosteroids (not good for maintaining remission), immune modulators for not weaning of cortico

Bio: mabs (TnA, anti integrin, anti IL), and small molecule biologics (JAKs, S1p)

Mesalamine MOA, ADEs, dosing?

ADes: Leakage with enema, localized bloating/pain

Have an enema and suppostiory form

FOR UC ONLY for left side disease only really

Oral ASA overall ADEs and bad in what way?

Slower to induce remission and more ADE than rectal 5 asa

ADE: headache, dyspepsia, rash diarhea

Azo bonded prodrugs 2, and caveat for olsalazine?

Olsalazine is 2 azo bonded molecules, strong, so diarrhea is DOSE RELATED AND TREATMENT LIMITING

Also have balsalazide (Bonded to inert carrier)

Delayed release 5 asa oral special how? (Asacol, pentasa, lialda)

Asacol: target terminal ielum and colon cause enteric coated

Pentasa capsules: Microspheres inside semipermeable membrane, retains water in intestine, and becomes slow release gel, so target duodenum, jejunum, ileum and colon

Lialda: enteric coated with 5 asa inside lipophilic matrix around hydrophilic matrox, slow release gel target only ileu and colon

SulfaSALAzine MOA, absorbed how, bad in what way?? DDIs and CIs?

5 azo bonded to sulfa pyridine, sulfapyridine absorbed systemically once 5 asa is released BAD

ADEs: Dose related: n/V, anorexia, diarrhea, folate malabsorption

Non dose related: rash, anemia, decreased sperm, BONE MARROW SUPPRESSION, hepatitis

Dis: ABX, decreased absopriton of folic acid/ferous sulfate, displace highly protein bounddrugs by sulfapyridine

CI with SULFA ABX ALLERGY

Corticstoeirds treatment limiting ADEs, what is preferred agent, and used how? WHAT IS LENGTH LIMIT

Fluid retention, moon face, hyperlipidemia, caracacts, osteo, muscle pain, increased infection, glucose intolerance

Budeosnide > prednisone or prednisolone cause more 1st pass so less systemic exposure

Compared to prednisone: less moon face, muscle pain and AEs

Cortico good for INDUCING remission BUT NOT MAINTAINING

used to control flares as bridging therapy until immunodmoulator work

SHOULDN'T USE > 8weeks for boht oral and rectal

immune modulators description

Steroid sparing, can maintain remission during cortico wean: needs 3-6 months of chronic dosing to become effective doe (so not good for inducing remission)

Can stop cortico after, but continue modulator for life

Indicated to decrease immunogeneicity with anti TNF a MAbs

Have AZT, 6MP, MTX

AZT or 6MP ADEs (non dose vs dose related), dosing TLDR< and test what for 6mp?

Non dose: PANCREATITIS< rash, n/v

Dose: bone marrow suppression, hepatitis

increased cancer risk

Chekc CBC q 2 weeks during induction, q 3 months during maintenace

TPMT testing with azt or 6mp: Poor metabolizers have risk of fatal myelosuppression

Some are rapid metabolizers meaning they can have therapeutic failure

MTX vs 6MP aDEs and dosing how monitor?

Works faster and less cancer than the other two

ADEs: Allergic (Interstitial pneumonia), leukopenia, hepatic fibrosis

SO monitor chest xray, CBC and liver functiont est

anti TNFa agents/Mabs class warnings

Incresed risk of tuberculosis, infections, cancer risk...? (Controversial)

lupus like syndrome

New onset of CNS disease or congestive heart failure

Reactive HBV

Infliximab description, can add what, ADEs (1 big), formulations?

Chimeric Mab (increased risk of infusion reactiona nd decreased efficacy if have immungenicity), can add immune modulators to decrease antibody formation

ADEs: Acute infusion reaction, delayed infusion reaction, and rare bone marrow suppress and severe liver tox

Give q 8 weeks

have IV and SQ

Certolizumab description, ADEs eh, dosing?

Pegylated HUMANIZED mab

ADEs; Upper respiratory infections, fever, HTN, fatigue

0, 2, 4 weeks for induction and then q month SQ

SQ so no infusion reactions

Adalimumab description ADes, dosing?

Human Mab

sinusitis and naso oof common

0, 2 week and then q 2 week to maintain

LOTS OF BIOSIMILARS

IS SQ

Golimumab Description ADEs, dosing?

ADes; upper respiratory oofs, increased liver enzymes, constipation, dizziness

Week 0, q 2 weeks then q 4 weeks for maintenance

Have SQ and IV (iv not for UC doe)

Vedolizumab moa, indications? ADEs (Good how?)

Integrin inhibitor (target a4b6 integrin in gut, so no inflammation can stick)

Indications: moderate-severe active UC/CD

ADes: Upper respiratory oof, fatigue, headache, etc. NO INCREASED CANCER RISK THOUGH

SQ

026, and then q 8 maintain

Ustekinumab MOA, indications, ADEs (gotta test what)? dosing?

Bind Human anti il2 and il23 human MAB

For moderate to severe CD patients who failed immunoimodulator/corticostoierds but not TNF blocker,s or in those who failed 1+ TNF blockers

ADes: reactivation of fungal infections, like latent TB (GOTTA TEST AT BASELINE)

Increased cancer risk

reversilbe posterior leukoencephalopathy syndrome

Risankizumab MOA, ADEs, precautions (imp) dosing? Use?

SElective anti IL 23 Mab

ADE: infection, liver tox, ab pain

Precautions: HYPERSENSITIVITY, ACTIVE TB

ONLY FOR MODERATE TO SEVERE CD, NOT UC

Mirikinzumab MOA, indications, ADEs, dangers?

SElective anti IL 23 Mab

ADE: infection, liver tox, ab pain

Precautions: HYPERSENSITIVITY, ACTIVE TB

Used for moderate- severe active UC OR CD

So very similar to risan but diff for indications

Guselkumab MOA, indication? Dangers? (2 important, special risks and avoid what), dosing?

Selective il23 human IMMUNOGLOIBULIN lambda mab

For severe active UC /CD

ADEs: Most common, upper resp infections, headache, fever, rash, arthrlagia

Precautions: HYPERSENSITIVITY< INCREASED INFECTION RISK, TB REACTIVATION< LIVER TOX

AVOID LIVE VACCINES

Selective JAK inhibitors Class AEs/BBW how, and DDIs?

BBW for:

Serious infections, lymphoma/tumors, increased risk of CV death, MI, stroke

Increased risk of DVT PE and embolism in those with 1 risk factor

Hyperlipidemia, acne, etc.

DDi with cyp3a4

Tofacitinib indication, dosing...? What not use with?

Is a JAK inhibitor

For moderate to severe active UC in adults who failed at least 1 anti TNF a agent

DOsing eh, but is ORAL NICE

SHOULDN'T USE WITH OTHER JAKI, bioligocs, or immunosuppressants

Upadacitinib indication, warning?

Is a JAK inhibitor

For moderate to severe active UC in adults who failed at least 1 anti TNF a agent

DOsing eh, but is ORAL NICE

SHOULDN'T USE WITH OTHER JAKI, bioligocs, or immunosuppressants

S1p Modulators indication (SPECIAL), DDis? Cis?

For adutls with moderate to severe active UC BUT NOT CD

DDis with CYp3a4

CIs: MI, heart stuff, AV block. Any heart sisue basically

Ozanimod and etrasimod ADEs

Ozaimod: common: upper respi, increased LFTs, headache

Rare: progressive multofical leukencoephloapthy, AV conduction delays, HTN

Etrasimod: Common: Headache, increased LFT< arthralgias,

Less common: HTN, UTI, herpes, hypercholesteremia, skin rash

Rare, (Same as ozani)

BOTH ARE PO, but ozani has an induction phase

How treat proctitis/eft sided UC (induction) (2 agents, and 2 week vs 2-4 weeks)

Is low risk/mild moderate active UC

Induction is rectal mesalamine qhs (oral less effective but ppl nonadherent to rectal)

if no improvement at 2 weeks, increase to rectal BID, or add cortisone suppositories QD and reduce mesalamine back to QHS

If no improve at 2-4 weeks: add oral meslamine or add oral budesonide MMX ore prednisone

How treat proctitis/eft sided UC (Maintenance)

Is low risk/mild moderate active UC

CAN'T USE CORTICOSTEROID FOR MAINTENACE

Preferred treatment: rectal mesalamine QHS and if oral mesalamine was used for induction, then only do oral mesalamine

Total 8 week corticosteroid course possible, with WEAN INCLUDED

Extensive UC (high risk/mild moderate active) Induction how? (4 things for alts) (thing stronger)

Standard dose oral mesalamine+rectal mesalamine

Is no improve at 2-4, then do oral mesal+recal corticstoierd, or add budesonide MMX (taper)

Or, can replace budeosnide with oral prednisone, and then taper

Maintenance of extensive UC how? 2 Add what thing to normal?

If oral mesalamine remission was achieved, stop rectal mesalamine and cont oral mesalamine at same dose

Steroid dependence: Can't wean corticosteroid without relapse, so start long term biologic

moderate-seevere active UC induction how? (2 for main (a dn alts?), and what do for relapse? test what?)

inflix trough level, adali and cetro?

If no antiboides, sub therape, no and therape, neutralizing and sub, neutralizing and thera?

First option: Anti TNF MAB+Immodulator (AZT preferred)

1-8 week response, can add oral prednisone for symptoms

MTX use if bad response to thiopurines

Cause use vedolizumab isntead of anti TNF for those with high risk of cancer

Ustekinumab preferred in patients unresponsive to AZT before

If have non responder/relapse test for: anti MAB antibodies, trough levels

Inflix:>5, adali>7.5, cetro>20

If no neutrlizing antibodies and sub therpaeutic trough:increase anti tnf dose

If have no antibodies and therpaueitc trough: change to alternate biologic drug class

If neutralizing antibodies and sub trough: low antibody level just increase dose,, if high change class

If nuetralizing and therapeutic trough: change to alternate class

Treatment of moderate to severe ACTIVE UC (top down therapy?) What agents high and low??? FOr treatment naive? Notes on Vedo and anti IL and Jaks?

Part of top down therapy (Early use of biologics/immune modulators)

Treatment naive: Choose high or intermediate efficacy agent:

high: INflixmab, vedolizumab, ozani or etrasimod, risaknizumab, guseklumab

interemdiate: golimjum, usetku,mirkizu

Low: ADALI SO DON'T USE (requries longer duration for response)

Vedolizumab and anti IL have LOWER INFECTION RISK THAN ANTI TNF MABs

Jak only for those who fail/can't teolrate anti TNF mab

Treatment of moderate to severe ACTIVE UC (top down therapy?) What agents high and low??? FOR PRIOR ANTI TNF MAB FAILURE/intolerance

Part of top down therapy (Early use of biologics/immune modulators)

Choose high or intermediate which are:

HIgh: tofacitinib, upadacitinib (JAKs), usektinumab

intermediate: mirki, riska, gusel

Low; adali, vedoli, ozamimod and etrasmiod

JAK i have higher risk of CV AEs and cancer than anti TNF in older adults, limited safety for JAK and S1p in pregnancy

Can use inflix or goli as last resort for top down therapy

Combo therapy for moderate to severe active UC how? Desslcate how?

If doing mono: Thiopurine/TMX NOT GOOD FOR MONO, but can use mono thiopurine to MAINTAIN remission for cortico induced

Combo with anti TNF: combo of modulator+biologic is preferred over monotherapy (but no evidence for combo with non anti TNF mab over non anti TNF mab monotherapy)

Stop 5 ASA once patient escalates to this combo

After 6 months of cortico free remission, DO NOT STOP ANTI MAB, and do not stop immuen modulator either

Severe-fulminant UC how treat for induction? (Severe vs fulminant diff) think ster

SEvere: preferred is budesonide or prednisone to remission

If don't respond, then can do IV methylprednisolone ir Hcortisone IV until stable and then switch to oral corticosteroid

Add azt, 6mp, inflix, certoli, adali, vedoli or tofacitinib and attempt steroid taper after 1-2 months (cause no 8 weeks

For fulminant: If don't respond, then can do IV methylprednisolone ir Hcortisone IV until stable and then switch to oral corticosteroid

If no response after 3-5 days, infliximab or cyclosporine Iv to remission

Maintenance for severe-fulminant UC?

Severe: AZt, 6mp or anti tnf mab (Mono)

Fulminant: Continue inflixi, vedozilu, or contineu oral cyclosporine with azt or 6mp

UC prognosis: goal and risk factor how?

Sustain steroid free remission

Most have mildly active disease that cna be managed with long term mesalamine

Left ove are risk of steroid depndence, surgery (and even with surgery can still come back)

UC is risk factor for colon cancer

how treat mild CD with low risk of progression? (limited to ileum and colon) induction vs maintenance)

Induction: Budesonide Enteric coated for 4-8 weeks preferred: if no response then switch

Maintenance: No relapse on budesonide, follow up colonoscopy at 6-12 months

If relapse on budesonide taper, then restart budesonide (with taper over 3 months)+ immune modulator

how treat mild CD with low risk of progression? (Diffuse/Distal colonic involved) induction vs maintenance)

Induction: PREDNISONE for 1 week PO, then taper over 1-2 months, if no response at 1 week then switch

maintain: no relapse on prednisone taper then monitor and follow up with colonoscopy at 6-12 months

If relapse, restart and add immune modulator

How treat moderate to severe active CD with moderate-high risk of progression (Induction) (if have fistula vs no fistula and alts) (Monotherapy when?)

If have perianal/intestinal fistula present: Then anti TNF mAb+immunomodulator (AZT preferred) (can use MTX as sub if patient can't take thiopurine OR HAS ARTHRITIS

Vedolizumab monotherapy for >60 yo or hx of cancer or infections

No fistulas then: anti TNF mab+AZT or vedolizumab monotherapy (COrticosteroid for more rapid symptomatic relief)

Usetiknu mono for biologic naive patients

if failed before can do Ustekinumab+azt or MTX

Riskanizumab nonotherapy good now also lol

How treat moderate to severe active CD with moderate-high risk of progression (maintenance)

If patient achieved remission on anti TNF mAb+ immunomodulator, then cont combo for 1-2 years , then try to stop immunomodulator based on evaluation of activity

Most high irsk patients need lifelong maintenae though

If relpase on anti TNF mAb maintenance: test for neutralizing antibodies and trough level

Thiopurine mono can be used in those who got remission on corticosteroid or relpased on biologic

Induction therapy for hospitalized patients with severe to fulminant CD how? (1 drug and 1 consider) similar

IV methylprednisolone is FIRST LINE

ANti TNF a can be considered (most is with infliximab)

Treatment of perianal or fistulizing CD (what is 1st line?) 2 alts/add ons

Anti TNF a are 1st line for perianal (not so much for fistulas), is mostly infliximab or comb of infliximab+metronidazole

Thiopurine for perianal or fistulas

METRONIDAZOLE FOR PERIANAL FISTULAS

Prevent CD recurrence in post surgery how? (No risk factor, vs normal, vs good alt?) high risk what?

Mesalamine maybe if have isolated ileal resection with no risk factor for progression

Metronidazole otherwise for small intestine resection

Thiopurine effective at preventing clinical recurrence, but can't stop severe endoscopic recurrence

In high risk patients: anti TNF a should be started within 4 weeks of surgery (add immunodulator maybe)

CD Prognosis and 2 bad drugs for CD

Highest activity during first year after CD diagnosis

Without immunomodulator/biologic agent: Most patients become steroid dependent/refractory YIKES

Up to 80% of patients need hospitalization,

10 year risk of surgery is 40-55% (low as 30 with biologics)

5 year rate is 50%

10 year risk of 2nd surgery is 30-35%

NSAIDS and smoking can increase disease activity

Stress can also and decrease qol and adherence.

Liver store what and excrete what and protect how

Glycogen, ADEK and B12 vitammins, iron, copper.

Excrete Bile, IGF-1, blood proteins, cholesterol, fatty acids, makes coagulation factors too.

Purify, transform and clear stuff

Kupffer cells are residential macrophage.

Collects portal blood from GI tract

Acute vs Chronic Hepatitis

Occurs at different degrees.

Cell injury is less in acute phase, but biggest difference is FIBROSIS

CHronic, you ALWAYS SEE FIBROSIS

Acute just have normal inflammatory infiltrate and macrophage.

Nomenclature for liver disease

Is now MASLD (used to be nonalcoholic fatty liver disease)

Have Alcohols use disroder and related liver diseases

(used to be alcoholic fatty lvier disease)

ASH and MASH descriptions (what have)

A:Alcoholic, MA: Metabolic dysfunction associated steatohepatitis

Both have fat, macro vesicular steatosis: big lipid droplets filling up liver.

Also have micro steatosis(initial response to damage)

Also have inflammation for sure, like Kupffer cells, T cells, NK cells, etc.

MASH: Lots of big white cells (Lipid droplets), can be irregular shape which is glycogen. Blue dots=inflammatory infiltrates.

Also have Mallory-Denk bodies: Are like cores of protein aggregates that can't be destroyed. Also have chicken wire fibrosis

MASH characteristics 6 (bigger how? deaths and stuff, and conditino of patient?)

Form of NAFLD

Steatosis, lobular inflammation, hepatocyte ballooning (accommodate death and growth), fibrosis (mainly chronic), metabolic syndrome

MASH Prevlanece in US

30-40% of population has simple steatosis, fatty liver disease is most common cause of abnormal liver tests.

20% of patients have MASH, and a little of cancer.

Liver lipid homeostasis

If eat a lot of simple carb, and liver breaks down the acetyl COA into FFA, and incorporate into VLDL out of liver. IF not excreted out of liver, have lipid accumlation.

If eat a lot of fat, fat from adipocyte will release into circulation and then taken up by blood and also cause lipid accumulation.

If lipid not excreted readily get fatty liver that way.

If no food eaten, get ADP, no oxidation and ketone body formation can occur. So can have lean fatty liver disease, dysfunction of mitochondria.

If have decreased beta oxidation and lipid transport, then ggs.

Two hit theory:

First hit: fat accumulate in liver (obesity/long term fasting)

second hit: injury leads to inflammation (Drugs, pathogens, leaky gut, genetic oofs, oxidative stress)

Alcoholism and alcohol use disorder

Basically get addicted to it, have binge drinking and all that.

Seeking that alc.

Seeking alcohol and binge drinking.

ASH Pathophysiology (lots of damage 3 things)

Similar to fatty liver with hepatic fat storage but also have:

Inflammation: increased hepatic uptake of gut derived endotoxins (like fungi, that stuff trigger liver first) trigger Kupffer cell activation and release factors

Oxidation: Induce CYp2E1 make toxic acetaldehyde and ROS

ER Stress: Ethanol mediated ER stress, cause protein mis folding.

Alcohol increased fatty acid synthesis and less oxidation, and activate innate immunity

Liver Fibrosis how? bad?

Persistent HSC activation, fibrosis is potentially irreversible.

Keeping on producing those fibrinous materials around cells with chronic inflammation: good at first since it seals and walls off damaged area to localize repair, but too long and too much is bad.

Eventually lower hepatic blood flow, numerous seequelae

And eventually need lvier transplantation

Cirrhosis induced by MASH

Some just stay in fibrotic state, never go into cirrhosis, but get early carcinoma. REALLY DANGEROus cause hard to diagnose those people

NASH features may not be seen like balloon and stuff, but fibrosis is still there

Algo for diagnosing steatosis liver disease

Check metabolic syndrome (BP>130/85, TG>1.7, HDL

Then calculate FIB4 index for fibrosis (liver function+platelet count/smth).

Then check how much alcohol take:

If not much is MASLD

More than metALD: (both alcohol+metab)

if A lot: Straight ALD

If none with no risk factors is MASLD or cryptogenic

How treat MASH/ASH-1

Reduce weight through exercise and diets (Japanese)

Treat T2DM

Reduce/do not drink ETOH

Avoid drugs/toxins with liver injury (DONT DRINK WHILE SICK)

Avoid pathogens/drugs with gut injury

Resmetirom MOA DDIs??

Ligand of thyroid hormone receptor beta, is a prodrug metabolized in liver

Improve hepatic conversino of T4 to T3 and help mticohondrial function

THRB is in liver, kidneys, pit gland and brain

Avoid alpha receptor since cause heart and bone ADEs (receptor in heart)

OATPB1 substrate so DDI with statins

Have some GI effect. Not a perfect drug.

Used for MASH/ASH-2

Semaglutide and MASH w/ fibrosis

Approved in 2025, and GI and GS side effects.

Now indicated for MASH

Reduce inflammation and stuff nice.

How prevent cirrhosis in patients with MASH, 2 drug classes and HOW FOLLOW UP FOR SURGERY

Lose weight and exercise and diet. (restrict sodium to stop volume overload)

Use GLP-1s in stage F2-F3 fibrosis (semaglutide has actual indication, others are off label: want to lose 7-10% of body weight)

Resmetirom: Can use if reach F2-F3 and failed GLP-1 therapy

Can also do bariatric surgery, but can have worsening of fibrosis, gotta monitor closely:

Monitor liver at 6 weeks, 3 months and 6 months; if have compensated cirrhosis follow up at 1 and 3 months.

Semaglutide good how, dangers/AEs (Cancer, pan, k, t2, brain)

Dis? (hypo and oral drugs)

Improve metavir fibrosis staging

Risk of thyroid C cell tumors, acute pancreatitis, AKI 2nd to volume depletion, diabetic retinopathy in t2DM, suicidal behavior/ideation. CLASS WARNING

DI with insulin and sulfonyulrea

Delay GI emptying time, so rip absorption

Resmetirom ADEs and DIs? (What cyp)

Liver tox, gallbladders

AVOID USE WITH MDOERATE-STRONG CYp2C8 INHIBITOR (Gemfibrozil, clopidogrel)

2nd line to GLP-1s

What wanna get from fluid/paracentesis

Want cell count/WBC, Albumin, Protein, culture negative

and also check Sodium conc from urine.

Cirrhosis lab values HVPG, and how diagnose decompensated? (2 big, 1 increased risk)

Defined by portal hypertension, so have ascites/volume overload, variceal bleeidng, hepatic encephalopathy

3-5 is normal

>5-10 is portal HTN

BUt >10-12 is CLINICALLY SIGNIFICANT HTN (is compensated cirrhosis): can have varices, risk of progression to HCC and decompensation

>12: decompensated esp, (Decompensated ONLY IF HAVE ONE OF THE 3 ISSUES):

Formation of ascites: most common presentation

increased risk of variceal bleeding

hepatic encephalopathy

Staging of cirrhosis 4 ways

Metavir score: same f1-F4

Child Pugh score

Fib4 (1.3 ok, 1.3-2.67 intermedaite risk, >2.67. high risk)

Presentations of cirrhosis symptoms?

OFten asymptomatic until decompensation occurs

Have nonspecific like anorexic, fatigue, GI

Jaundice, hepatosplenomegaly

Gynecomastia, testicular atrophy, spider nevi, palmar eryhthema

astirexis

Labs of cirrhosis?

Low BUn and ALbumin, low blood, prolonged INR (normal is 0.8-1.1), increased ammonia (usual is 10-32, comes from breaking down protein, want to reduce pH so have more ionized ammonia so it can be absorbed)

Liver enzymes

3 ways to diagnose cirrhosis

Imaging

Biopsy

Noninvasive methods: Pugh score, meld score

Cirrhosis specific complications how treat (Decomp, vari, ence, read, HCC)

CARVEIDOLOL FOR HEPATIC DECOMPESNATION,

Carvedilol for variceal complication or IV ABX

Lactose for hepatic encephalopathy (+/- rifaximin)

Hospital readmission: Multi modal discharge interventions

HCC: Check, NO ASPIRIN

Non liver specific complications (Osteo, cancer), infection prevention an dlifestyle factors?

Osteo: Screen dexa, bisphopshonates

Screen for cancer, and make sure they vaccinated

Exercise, good nutrition, NO ALCOHOL, stop smoking

Cirrhosis management

Only definitive treatment is liver transplant, everything else is supportive

Treat underlying cause, and manage complications

BP SUPPPORT: If MAP

MELD Score

Accoutns for gender, biliburin, Na, Albumin, INR, Creatinine

If have 30-40: SIckest patients, high prio for liver transplant

if 25-40 recheck every 7 days HIGH CHDNACE OF DEATH

if 19-24, recheck in 1 month

11-18 q 3 months 6% chance of death in 90 days

6-10 q 1 year, mild

Stage 1-5 for MELD

1: compensated cirrhosis no varices

2: Compensated with varices

3: Decompensated with ascites

4: Decompensated cirrhosis with IG Bleed

5: Infection/hepatorenal snydrome/renal failure

Ascites presentation and symptoms

Can also have hepatic hydrothorax where fluid leaks into pleural cavity, not peritoneal like asites.

Ab distention with firm abdomen shifting on palpation

Increase ab rith and 15 lb weight gain according to patient HX

5L of fliud removed by parancentesis, ingest 88mEq Na but only excreting 50

Ascites MOA

Increased portal venous pressure and decreased plasma oncotic pressure (albumin determine this)

IV volume depletion and decreased renal perfusoin leads to increased plasma renin activity (retention)

Use non selective beta blocker if HVPG Is high TO PREVENT ascites, not treat

How manage ascites (alc, Na how much, what drug x2)

What drugs to avoid?

ALCOHOL ABSITENENCE

Sodium restriction (88mEq/day)

Diuretics: Combo of spironolactone+Furosemide

NO NONSELECTIVE BETA BLOCKER esp for advanced cirrhosis where MAP going down

ACEi ARB (rip kidneys)

NO NSAIDS

or nephrotoxicd rugs

Protect kidney