HEPATOLOGY

Editor: Vanessa I. Rodriguez, MD
Reviewed by: Manhal J. Izzy, MD

Cirrhosis Overview

Author: Ahmad Yanis

Background

Example 1-liner: 65yo M with cirrhosis due to HCV decompensated by ascites and HE (MELD 25) who is listed for transplant and followed by Dr. Izzy

Cirrhosis due to	Compensated / Decompensated by	MELD-Na	Transplant Status	Followed by

Etiology of cirrhosis: HCV>HBV, EtOH, NASH, Wilson's, hemochromatosis, A1AT deficiency, autoimmune hepatitis, PSC, PBC, congestive hepatopathy (right heart failure), medication-induced
Complications that cause decompensation: overt ascites (or hepatic hydrothorax), overt hepatic encephalopathy (HE), esophageal variceal hemorrhage (EVH)
Always calculate daily MELD-Na scores (predicts 3 mo survival based on Tbili, Cr, INR, Na)

Evaluation

Goals: establish etiology, evaluate/treat complications, determine prognosis, and consider transplant evaluation

History:

Symptoms suggesting decompensation: confusion, sleep disturbances, abdominal swelling, lower extremity edema, scleral icterus/jaundice, pruritus, easy bruising/bleeding (skin, mouth, GI tract), dyspnea
Social history: EtOH and drug use hx, date of last drink, average # of drinks/day, duration of EtOH use, prior rehab, hx of DUI, if there has been continued EtOH use despite knowledge of liver disease; these factors all impact transplant candidacy
Ascites: compliance with diuretics, compliance with salt restriction, frequency of paracentesis (volume removed, date of last para), h/o SBP, hx of TIPs
HE: compliance with lactulose, # of BMs per day, any potential triggers (see HE section)
GIB/EVH: hematemesis, coffee ground emesis, melena, hematochezia (duration, volume, # of bleeding episodes), last EGD (varices, banding) and colonoscopy, compliance with non-selective BBs

Physical exam:

asterixis, ascites, edema/anasarca, splenomegaly, muscle wasting, gynecomastia, testicular atrophy, palmar erythema, spider angiomata, scleral icterus/jaundice, petechiae/ecchymoses, caput medusa, Terry's nails

Labs

Initial Workup: CMP, CBC, Coags, UA, HCV/HBV, Fe studies, PEth
Unless requested by hepatology, defer to outpatient: AFP, ANA, IgG, A1AT, ceruloplasmin, AMA (PBC), ASMA (AIH), anti-SLA (AIH), anti-LKM (AIH)

Imaging:

Abdominal US with duplex unless done in past 6 months or indication for repeating sooner (concern for new portal vein thrombosis)
For transplant eval, needs triple phase CT A/P (contrasted study, arterial and venous phases) or MRI abdomen with contrast

Liver biopsy:

gold standard for cirrhosis diagnosis but is not always needed if clinical presentation, labs, and imaging consistent with cirrhosis

Lab abnormalities

Hyponatremia (see hyponatremia section below)
Cirrhotic coagulopathy (increased INR): due to ↓ coagulation factor production
Thrombocytopenia: due to splenic sequestration, ↓ TPO production
Hypoalbuminemia: indications for 25% albumin transfusion – SBP (1.5g/kg on day 1, 1g/kg on day 3), LVP (6-8g/L of ascites), HRS (albumin challenge: 1g/kg/day with max 100 g/day x 2 days), hypoNa <125 and refractory to fluid restriction

Management

Nutrition:

High protein diet, 2g Na restriction (if ascites present)
Consider MVI, folate, thiamine (particularly in pts with EtOH use disorder)
Mediterranean diet for NASH
Fluid restriction if hyponatremic

Immunizations:

ensure UTD with HBV/HAV, PPSV23, Prevnar, Flu, COVID-19 vaccines

Additional Management:

Consider consulting Addiction Psych and Social Work for pts with EtOH use disorder - can assist with arranging Intensive Outpatient Program (IOP), Alcoholics Anonymous (AA)
General screenings include HCC screening (q6 months), EVH screening (see section below), monitor for other decompensations and treat accordingly, monitor MELD and consider transplant evaluation when >15
Refer to hepatology outpatient

Medication Tips

Pain:

2g limit Tylenol, No NSAIDs, limit sedating medications especially with HE. - Tramadol 25-50mg generally safe to use

Pruritus:

Sarna lotion, can spot dose antihistamines. Can discuss with pharmacist/attending about starting sertraline, cholestyramine (interacts with many medications), or rifampin.

Anxiety/insomnia:

hydroxyzine, avoid benzodiazepines

EtOH withdrawal:

If needed for EtOH withdrawal, use lorazepam (Ativan) instead of chlordiazepoxide (Librium) or diazepam (Valium) due to its shorter half life

Liver Transplant (LT) Workup

Author: Katelyn Backhaus

Background

Model for End-stage Liver Disease (MELD-Na) score: initially developed to predict survival following TIPS placement, though is now used to objectively rank patients in terms of priority for liver transplant (LT)
Factors in total bilirubin, creatinine, INR, and Na.
Exception points given for complications like HCC and hepatopulmonary syndrome (HPS), leading to score in mid to high 20's even if biologic MELD is low
Highest score lasts for 7 days
Listing a pt for LT is determined by a multidisciplinary transplant committee
Acute liver failure pts take precedence over decompensated cirrhosis pts for LT

Indications and Contraindications

Indications:

Cirrhosis with MELD ≥ 15 or evidence of decompensation (ascites, variceal bleed, HE, HPS, portopulmonary HTN)
Acute liver failure
HCC that meets Milan criteria
Pts with early hilar cholangiocarcinoma that meets specific criteria
Other rare diseases (e.g., familial amyloid polyneuropathy or hyperoxaluria)

Contraindications*:

Ongoing substance abuse (must have documented abstinence ≥ 3 mos) – refer to exception policy in Alcoholic Hepatitis section
Untreated or recurrent malignancy or metastatic disease
Active infection, AIDS (CD4 <200)
Documented history of medical noncompliance
Lack of adequate social support
Anatomic contraindications: chronic cardiac/pulmonary conditions that significantly increase perioperative risk (e.g., severe pulm HTN)
Fulminant hepatic failure with sustained ICP >50mmHg or CPP <40mmHg
Class III Obesity (BMI>40) is a relative contraindication (class 2B)

*Advanced age (>70) is not itself a contraindication but candidates >70 should be almost free of comorbidities to be considered

Evaluation

Abdominal CT (triple phase) or MRI (multiphase with contrast) to evaluate for hepatic malignancy and vascular anatomy
Infectious workup: TB testing, HIV, RPR, VZV, CMV, EBV, and Hepatitis A, B, and C
Cardiac evaluation: [see flowchart in physical handbook]
If RVSP > 40mmHg on TTE, then R Heart Catheterization is indicated
PFT's, carotid US
Panorex to identify dental disease; consult OMFS pending results
Appropriate cancer screenings (CXR in all patients, CT Chest in prior/current smokers, colonoscopy, pap smear, mammogram, and PSA if applicable)
DEXA scan (osteoporosis in up to 55% of individuals with cirrhosis)
Certification of completion of intensive outpatient program (IOP) for substance abuse
Evaluation by hepatobiliary surgical team after obtaining cross sectional imaging
Psychosocial evaluation (consult Psychiatry, social work)
Current VUMC policy: pts should be abstinent from alcohol for no less than 3-6 months, although exceptions may be made for early liver transplant based on a very strict protocol. Discuss exception criteria with attending if suspect patient unlikely to survive hospitalization without transplant

Note: Both living and deceased donor transplants are offered at VUMC. Donor evaluation, however, cannot be started before the potential recipient is deemed a candidate. Of note, should consider possible simultaneous liver-kidney transplantation for 1) CKD <30mL/min after > 90 days of eGFR<60 or 2) AKI dependent on dialysis >8 weeks or if extensive glomerulosclerosis present.

Spontaneous Bacterial Peritonitis (SBP)

Author: Bailey DeCoursey

Background

Infection of ascitic fluid without evidence of a surgical intra-abdominal source
Present in approximately 1/3 of patients with cirrhosis who are hospitalized
Presentation: fever, abdominal pain, encephalopathy, renal failure, acidosis, and/or leukocytosis. However, up to one-third of the patients with spontaneous infections may be entirely asymptomatic or present with only encephalopathy and/or AKI
Pathophysiology: Combination of GI bacterial flora overgrowth, reduced liver protein production (low complement levels), impaired phagocytic cell function leading to inability to clear pathogens

Evaluation

Any pt with cirrhosis and ascites who is admitted should have diagnostic para to r/o SBP. Delaying paracentesis > 12 hours is associated with a 2.7-fold increase in mortality.
Obtain cell count with diff
Calculate the PMNs: total nucleated cells x % neutrophils.
PMN > 250 cells is diagnostic of SBP. If there are greater than 100k RBCs, you should correct for them: for every 250 RBCs, subtract 1 PMN
A positive ascitic bacterial culture with PMN <250 is called bacterascites and asymptomatic patients with bacterascites should NOT receive antibiotics as it is likely a contaminant (however, repeat paracentesis should be performed to exclude progression to SBP). You will also frequently see culture-negative SBP (neutrocytic ascites) which SHOULD be treated (see below).

Management

Immediate Treatment:

Immediately start empiric antibiotics
Guidelines recommend cefotaxime IV 2gm q8 hours x 5 days, but we commonly use ceftriaxone IV 2g q24h for 5-7 days at VUMC and Nashville VA
Most common culprits (E. coli, Klebsiella, streptococcal species, staphylococcal species)
If SBP developed with recent hospital admission (90 days), recent exposure to BSA, diagnosed >48 hours of admission, or with sepsis, should give zosyn +/- vanc if prior infection or positive swab for MRSA. Daptomycin should be added with hx of VRE infection instead of vanc.
Finally, in patients with current or recent exposure to zosyn consider meropenem for MDR coverage.
IV albumin 1.5 g/kg on day 1 and 1g/kg on day 3
NSBB do not need to be discontinued in patients with SBP unless hypotensive (mean arterial pressure <65mmHg). If stopped, the timing of re-initiation is based on recovery of blood pressure
PPI's ↑ risk for SBP in pts with cirrhosis, and should be reviewed for appropriateness
Repeat diagnostic paracentesis two days after antibiotics initiated
If <25% decrease in PMNs, antibiotics should be broadened. Consider secondary bacterial peritonitis.

Prophylaxis:

Acute prophylaxis: Ciprofloxacin 500mg BID (preferred) or Bactrim one DS tablet BID x 5-7 days
IV ceftriaxone 1g daily is currently the recommended antibiotic in patients with hemorrhage
Outpatient lifelong prophylaxis:
Prior SBP
Ascitic protein <1.5 AND Child Pugh >9 and bilirubin >3 OR Renal dysfunction (Cr >1.2, Na <130, or BUN >25)
Preferred: Bactrim DS tab daily or ciprofloxacin 500mg daily
Alternatives: cefdinir 300mg daily, Augmentin 875/125 daily

If suspicion is high for secondary bacterial peritonitis:

Examine serum-ascites albumin gradient (SAAG). SBP develops in pts with portal hypertension, defined by SAAG > 1.1 g/dL. SBP is unlikely if SAAG is < 1.1 g/dL.
While not particularly sensitive, an ascitic leukocyte count of 5-10k should prompt consideration of secondary peritonitis
Amylase from fluid can also be helpful to point towards pancreatic ascites, while bilirubin can indicate gallbladder perforation.
Peritoneal fluid CEA and alkaline phosphatase can additionally help identify hollow viscus injury.
Evaluate with cross-sectional imaging and surgical consultation as appropriate

Runyon's Criteria to distinguish, requires 2/3 criteria below (protein, glucose, LDH)

	Spontaneous	Secondary
Protein (g/dL)	< 1	> 1
Glucose (mg/dL)	≥50	< 50
LDH (U)	Elevated, but < 225	> 225
Organisms	0-1	Polymicrobial

Gastroesophageal Varices and Hemorrhage

Author: H. Anh Richardson

Background

Varices form due to portosystemic collaterals in the setting of portal HTN
Gastroesophageal varices are present in approximately 50% of patients with cirrhosis and their presence correlates with severity of liver disease
The risk of mortality with esophageal variceal hemorrhage (EVH) can be up to 15-20%
Recurrence occurs in over 60% of patients within 1-2 years of the index event
The most important predictor of hemorrhage is the size of the varices. Other predictors include decompensated cirrhosis (Child B/C) and endoscopic presence of red wale marks or red spots

Variceal Screening:

Regular screening not required in all patients with cirrhosis though initial EGD at time of cirrhosis diagnosis is recommended. Screening can be omitted in patients without evidence of clinically significant portal hypertension (low liver stiffness on elastography [LSM <20 and platelets >150], repeated TE annually) and in patients at low risk of bleed on NSBB.
Compensated cirrhosis without varices: EGD q3yr
Compensated cirrhosis with small varices that have not bled: EGD q2yr (unless on NSBB, then no need for follow-up EGD)
Decompensated cirrhosis: EGD at time of decompensated and then q1yr
Medium/large varices that have not bled: NSBB if tolerated (follow up surveillance EGD unnecessary) or EVL, repeated until obliterated with first surveillance EGD 1-3 months after and q 6-12 months to check for recurrence

In general, most patients with cirrhosis should be on propranolol or carvedilol (preferred due to intrinsic anti-alpha-1-adrenergic activity and facilitates the release of nitric oxide, induces intrahepatic vasodilation further reducing portal pressure), per new guidelines. Always check with the hep attendings if BB needs to be started.

Management (Non-Bleeding Varices)

Primary ppx with either NSBB (preferred if tolerated; see table below) or endoscopic variceal ligation (EVL). EVL indicated in patients with high risk of bleeding (medium/large varices, small varices with red wale sign, or decompensated patients with varices of any size).
Carvedilol has greater reduction in portal pressures and is preferred if tolerated (goal 6.25mg BID)
Nadolol (given nightly as portal pressures are highest at night) or propranolol (BID)
For secondary ppx, initiate ~72hr after acute bleed has resolved and octreotide discontinued
Discontinue if: hypotension (SBP <90), AKI-HRS, SBP, or hyponatremia with refractory ascites
Secondary ppx with both NSBB and EVL
NSBB are associated with reduced mortality, while EVL is not

Of note, in patients with clinically significant portal HTN but are without varices, there is no evidence to support the use of NSBB to prevent varices formation, but high-level evidence does support use of NSBB (strongest evidence for Carvedilol) in prevention of any decompensation (ascites, variceal hemorrhage, HE) and has a mortality benefit (likely driven by significant reduction in ascites development)

Management (Bleeding Varices)

Place two large-bore IVs (18G or larger), resuscitate with blood products and albumin. Activate massive transfusion protocol if needed.
Consider intubation if need for emergent EGD, change in mental status, ongoing hematemesis, or inability to protect airway
Start octreotide 50 mcg IV bolus followed by continuous infusion of 50 mcg/h, to be continued for at 2-5 days should EVH be confirmed on endoscopy
Ceftriaxone 1g IV q24h for SBP prophylaxis (reduced mortality), then transition to PO ciprofloxacin for total 7-day course
Consult GI for upper endoscopy for possible EVL vs sclerotherapy. EGD should be performed within 12 hours of admission.
Consider balloon tamponade with Blakemore as temporizing measure before definitive management. Patient must be intubated before placement, and preferably GI should be made aware prior to placement.
No role for the correction of INR, even in the presence of bleeding as excessive blood products and FFP can increase portal pressures and cause worsening bleeding
Vitamin K can be given w/ ↑ INR, though is unlikely to help in the acute setting
Check TEG and fibrinogen and transfuse based on results
AASLD does not recommend specific platelet targets during variceal hemorrhage
Administer blood products in balanced ratio to avoid transfusion related coagulopathy

Beta-Blocker Dosing Table

Therapy	MOA	Starting dose	Titration	Max dose	Goal
Propranolol	Decreased cardiac output; caused by decreased heart rate and contractility from beta-1 adrenergic blockade	20–40 mg twice daily	Increase the dose every 2–3 d until treatment goal	Without ascites: 320 mg/day; with ascites: 160 mg/day	HR of 55–60 bpm if tolerated; SBP should be maintained ≥90 mm Hg
Nadolol	Above plus Splanchnic arterial vasoconstriction; caused by beta-2 blockade leading to unopposed alfa-adrenergic vasoconstriction	20–40 mg at bedtime	Increase the dose every 2–3 d until treatment goal	Without ascites: 160 mg/day; with ascites: 80 mg/day	HR of 55–60 bpm if tolerated; SBP should be maintained ≥90 mm Hg
Carvedilol	Above plus decreased intrahepatic vascular resistance; caused by anti-alpha-adrenergic activity	6.25 mg once daily	Increase to 6.25 mg twice daily after 3 d	12.5 mg/day (higher doses could be considered for non-hepatic indications)	No HR goal; SBP should be maintained ≥90 mm Hg

Ascites and Hepatic Hydrothorax

Author: Thomas Strobel

Ascites

Background

Associated with a reduction in 5-year survival from 80% to 30%.
Most often due to portal HTN. Less common causes include peritoneal or metastatic cancer, CHF, TB, nephrotic syndrome, Budd-Chiari, sinusoidal obstructive syndrome (S.O.S), or complications from procedures and pancreatitis

Grade	Definition	Treatment
Grade 1 Ascites	Only seen on imaging	2g Na restriction
Grade 2 Ascites	Moderate, symmetric abdominal distension	2g Na restriction, diuretics
Grade 3 Ascites	Marked, tense abdominal distension	LVP + Na restriction, diuretics (unless refractory)

Evaluation

Bedside ultrasound on admission to confirm presence of ascites
Diagnostic paracentesis in all pts with ascites on admission mainly to rule out occult SBP
Initial paracentesis or when cause of ascites is uncertain: ascitic fluid total protein, serum and BF Albumin, cell count w/diff, culture
Subsequent/Serial paracenteses: cell count w/diff, culture, protein
Always inoculate culture bottles at bedside
Per AASLD guidelines elevated INR and thrombocytopenia (<50K) are not contraindications for paracentesis. Additionally, administration of clotting factors or platelets is not recommended. However, practically our procedure team often looks for INR < 3.5 (IR usually does not care about INR)
Serum-ascites albumin gradient (SAAG) = serum albumin - ascites albumin.

Total Protein Ascites (not serum)	SAAG ≥1.1 g/dL (Portal HTN)	SAAG < 1.1 g/dL (Non-portal HTN)
< 2.5 g/dL	Cirrhosis	Nephrotic Syndrome, Myxedema
≥2.5 g/dL	Post-hepatic portal HTN: Cardiac Ascites, Budd-Chiari	Malignant Ascites, Pancreatic Ascites, TB

Other tests:

Triglycerides: if fluid is milky
Cytology: if very concerned for peritoneal carcinomatosis. May need up to 3 separate samples (50ml or more) to be able to detect malignant cells
ADA: if concern for peritoneal TB
Hematocrit: For bloody appearing fluid (not just serosanguinous) to rule out hemoperitoneum. There needs to be a recent serum HCT for comparison.
Amylase: If concerned for pancreatic ascites
Glucose, LDH if concern about secondary peritonitis

Management

2000mg sodium restriction per day for all ascites (Grade 1-3)
Diuretics (spironolactone and typically furosemide)
Start at 100mg of spironolactone with up titration to 400mg
Furosemide is added if insufficient diuresis or if limited by hyperkalemia. Use more loop diuretics in patients with CKD.
If Urine Na:K ratio <1, indicates insufficient natriuresis. Can ↑ doses to a max of 400:160
If poor response can change to torsemide 10mg and ↑ to 40mg max (per single dose)
Fluid restriction usually not necessary unless serum sodium <125 mmol/L
Large volume paracentesis should be performed for tense ascites regardless of serum Cr. Pts with tense ascites should be tapped dry with each paracentesis (per EASL) and may consider an upper limit of 8 L (per AASLD, based on one study)
Give 6-8g of albumin per liter of ascites removed, even if < 5L
Target weight loss of 0.5 kg/day when diuresing to avoid renal injury
Discontinue NSAIDs and ACEI/ARB

Refractory Ascites:

Two distinctions: - Diuretic-resistant: lack of response to diuretics (max spironolactone 400mg/Lasix 160mg), Na restriction and rapid recurrence following paracentesis - Diuretic-intractable: unable to tolerate diuretic therapy due to adverse drug effects (unexplained HE, AKI, K abnormalities, hypoNa, intractable muscle cramps)

Management aside from liver transplant: - Discontinue diuretics once refractory ascites has been established, but continue Na dietary restriction - Consider oral midodrine; can be especially helpful if pt is also hypotensive - Serial paracenteses, generally arranged OP with IR - Consider TIPS (trans jugular intrahepatic portosystemic shunt; has survival benefit) for refractory ascites or recurrent ascites (>3 LVPs in one year despite compliance with diet and diuretics). Following TIPS, cessation or decrease in ascites should occur in ~6 weeks - Consider discontinuing beta blockers in patients with refractory ascites if sBP <90, SCr >1.5, or Na <130

Hepatic Encephalopathy (HE)

Author: Ahmad Yanis

Classifications of HE:

Type A: in patients with acute liver failure
Type B: in patients with portosystemic shunt without significant liver disease
Type C: in patients with cirrhosis
Covert HE: minor or no signs/symptoms but abnormalities on neuropsychological and/or neurophysiological tests
Overt HE: Clinically appreciable change In mental status (e.g., AxOx2 or asterixis) recurrent (≥ 2 bouts) within 6 months
Persistent: if the patient does not return to their baseline performance between bouts.

Evaluation

Asterixis: inability to maintain stable posture; many ways to assess

Check for clonus
Have pt "hold out hands like you are stopping traffic" (if following commands)
Shine light in pupil (look up video of hippus)

Grading Scale:

Grade	Behavior Change
I	Mild confusion, changes in behavior, increased sleep, no asterixis, cannot be confirmed without neuropsych testing
II	Moderate confusion, lethargic, AAOx2, +asterixis
III	Marked confusion, arousable but falls asleep, incoherent speech, AAOx1, +asterixis
IV	Coma

Identify precipitants:

Infection (rule out SBP in addition to CXR, BCx, UA/Cx)
Medication non-adherence (lactulose)
GI bleed (perform rectal exam and observe Hgb trend)
Over-diuresis resulting in dehydration, electrolyte abnormalities (especially hypoK)
Sedatives/benzo/opiate administration (UDS)
Brain imaging does not provide any diagnostic value for HE but may be utilized if diagnostic uncertainty exists

Increased ammonia (NH3) levels do not add any diagnostic, staging, or prognostic value in patients with CLD. A normal ammonia level, however, calls for diagnostic re-evaluation

Arterial NH3 is used in acute liver failure for prognostication (not for management)

Management

Always determine precipitant and treat underlying condition
Lactulose 30mL TID initially titrated to 2-3 BMs/D as secondary prophylaxis after the management of first episode of overt HE.
Titrate dose to at least 4 BMs daily, avoid excessive stool output which may exacerbate HE d/t dehydration and electrolyte abnormalities
Consider lactulose enemas vs DHT placement if pt unable to tolerate PO
- DHT are not contraindicated in patients with esophageal varices, but should be avoided in patients with recent hemorrhage or banding
Add Rifaximin after the second episode of HE, or if failure to respond to lactulose
- Frequently requires prior authorization for outpatient approval and is expensive
Consider the addition of golytely as it has been found in RCTs to expedite resolution of severe HE by 1 day
Lactulose is generally continued indefinitely after first episode of HE, though discontinuation can be considered on an individual basis if predisposing factors (recurrent infection, EVH, EtOH use) have resolved, improvement in liver function, and improvement in nutritional status
For patients with chronic diarrhea off lactulose, consider adding BCAA (0.25 gm/kg/d)

AKI & Hepatorenal Syndrome (HRS)

Author: Garren Montgomery

Background

Portal HTN causes shear stress on portal vessels → endothelium release of vasodilators → splanchnic vasodilation and reduced effective blood volume (decreased MAP) → RAAS activation → sodium and water retention and severe renal vasoconstriction
Bacterial translocation (as seen in SBP) increased circulating pro-inflammatory cytokines → splanchnic vasodilation

Definitions:

HRS-AKI (formerly type I HRS): Rise in Cr ≥0.3 within 48h, rise in Cr ≥50% within 7 days, OR UOP <0.5 mL/kg/hr for 6 hours
HRS-NAKI ("non-AKI") (formerly type II HRS):
HRS-AKD: eGFR<60 for <3 months in absence of other structural causes OR % rise in Cr ≤50% using last available Cr over last 3 months as baseline
HRS-CKD: eGFR<60 for ≥3 months in absence of other structural causes

Diagnostic Criteria:

Diagnosis of AKI (see above) without other cause (see below)
No response or inadequate response at 48 hrs after volume expansion with albumin (1g/kg/day) and withdrawal of diuretics
Absence of proteinuria (<500 mg/d), absence of hematuria (<50 RBCs per HPF), normal renal ultrasound (exclude if patient has known CKD)
Suggestion of renal vasoconstriction with FeNa <0.2, FeUrea <20 (most sensitive diagnostic measure). UNa <20 is suggestive but not diagnostic given baseline sodium avidity in cirrhosis and inability to calculate FeNa. If UNa Is <20, FeNa cannot be calculated.
Cut off for ATN in cirrhosis is a FeNa >0.5, rather than 1 in the general population

Evaluation

Step 1: Exclude other obvious causes of renal injury such as hypovolemia or ATN

Common precipitants of AKI: infection, over diuresis, GI bleeding, recent LVP without subsequent volume expansion, nephrotoxic drugs/NSAIDs
Workup: BMP, UA with microscopy, urine electrolytes (FeNa, FeUrea), urine protein/Cr ratio, renal ultrasound (to assess for chronicity), diagnostic para to rule out SBP

Step 2: Diuretic cessation/albumin challenge

STOP all diuretics, beta blockers, NSAIDs, ACE/ARBs, anti-hypertensives, vasodilators, nephrotoxins
START volume expansion with albumin 1g/kg/day (up to a max of 100 g/day) x2 days

Step 3: Diagnosis of HRS

If no other clear cause of AKI is identified and SCr has not improved after 48 hours of diuretic cessation and volume expansion, proceed promptly to vasopressor treatment

Management

Pharmacologic therapies (in order of preference):

Terlipressin (+/- albumin 50g/day, unless there is evidence of volume overload). Most effective medication based on randomized clinical trials, NOW FDA APPROVED and approved for use at VUMC in Transplant Candidates only. Titration is done based on creatinine response.
Alternatively, consider Norepinephrine (+/- albumin 50 g/day)
Requires central access (PICC vs triple lumen) but can be administered on stepdown unit
Guidelines recommend NE to be dosed at 0.5-3 mg/hr. Would ask fellow, attending or pharmacist for baseline. VUMC protocol for ICU and stepdown:
Start NE gtt at 3mcg/min. If UOP is <200 or MAP <10mm Hg from baseline, increase by 3 mcg/min every 4 hours
Continue to hold diuretics. LVP is still generally considered safe even in HRS if indicated by tense ascites (account for albumin repletion from LVP and HRS protocol). This can be attending specific and would confirm prior to performing
Therapy is generally continued until HRS is reversed or the hepatology attending deems it refractory to medical treatment. (Per guidelines, protocol normally discontinued if Cr remains at pretreatment level or above >4 days)
Patients with HRS-NAKI (formerly type II HRS) may respond to the above therapies, but recurrence of renal dysfunction after withdrawal of vasoconstrictors is the norm and thus current guidelines do not recommend them for this scenario

RRT:

Dialysis can be considered for those who fail to respond to pharmacologic therapy, particularly as a bridge to liver transplant. Decision to initiate should be individualized

Liver transplant:

The best and most definitive treatment regardless of response to pharmacologic therapy

Simultaneous liver-kidney transplant:

HRS often resolves with LT alone. Indications for kidney transplant are usually for patients with severe chronic renal dysfunction or on RRT. Must consult transplant nephrology.

Criteria for SLKT: - eGFR <60 for >30 days AND latest eGFR <30 - eGFR <25 for >6 consecutive weeks with a documented eGFR q7 days - Metabolic kidney disease and polycystic disease

Can qualify for safety net kidney transplant after liver transplant if eGFR <20 2-12 months post-operatively (would be at higher priority than the rest of the kidney transplant list)

Hyponatremia in Cirrhosis

Author: Kinsley Ojukwu

Background

Hyponatremia in cirrhosis is often defined as serum Na < 135 mmol/L
Very common problem; prevalence: ~50% of individuals have serum < 135 mmol/L, ~22% < 130 mmol/L
Degree of hyponatremia is associated with progression of cirrhosis; patients with hypona have greater incidence of HE, SBP, and HRS, increased complications & mortality pre/post-tx.
Patients most commonly have hypervolemic (dilutional) hypona.

Pathophysiology

Hypovolemic hyponatremia: 2/2 excessive diuretic use
Hypervolemic hyponatremia: Advanced cirrhosis → chronic inflammation and fibrosis in liver → increased resistance to portal flow → portal hypertension → release of vasoactive compounds (primarily nitric oxide) → splanchnic arterial vasodilation → reduced effective arterial blood volume (splanchnic veins contain 20% to 50% of the total blood volume) → reduced effective intravascular volume leads to activation of RAAS + ADH + sympathetic nervous system → RAAS encourages Na retention and ADH causes insertion of aquaporins in distal tubule and collecting duct to increase water reabsorption → dilutional (hypervolemic) hyponatremia

Evaluation

Uosm, Sosm, UNa to rule out competing processes (e.g. beer potomania)

Management

Do not correct Na faster than 6-8mEq/L in 24 hours
Discontinue anti-hypertensives (including beta blockers) in patients with ascites and hypona. Hold diuretics when Na <125
Fluid restriction is recommended only in patients with Na <125. Restriction is generally effective at 1-1.5L and must be less than daily UOP to increase free water excretion
Replete K to 4.0
25% albumin infusion (1g/kg split into BID dosing), has been shown to increase serum Na and have higher rates of hypona resolution at 30 days
Treatment considerations include vasopressors, urea tabs
Vaptans are generally not used in clinical practice given recent RCTs showing harm with use
Salt tabs should not be used to raise serum Na due to worsening hypervolemia
Nephrology should be consulted if not improved after 48 hours

Transjugular Intrahepatic Portosystemic Shunt (TIPS)

Author: Ahmad Yanis

Background

A TIPS procedure is done by IR to manage sequalae of portal HTN (specifically variceal bleeding and ascites)
A low-resistance shunt is created between an intrahepatic branch of the portal vein and the hepatic vein, allowing blood to bypass the high-resistance vessels within the fibrotic liver.
Ideally, creating the smallest-necessary caliber shunt is desirable. Recent studies suggest that an 8-mm-diameter PTFE-lined TIPS may be sufficient to prevent variceal rebleeding and potentially decrease the incidence of hepatic encephalopathy

Evaluation

Indications for TIPS:

Variceal hemorrhage (esophageal, gastric, etc.)
Early "preemptive" TIPS is an urgent TIPS placement within 72 hrs (preferably within 24 hours) of initial endoscopic hemostasis in pts at high risk for rebleeding (Child-Pugh Class B with active bleeding upon insertion of endoscope or Child-Pugh Class C with recent bleeding
"Rescue" TIPS is placed in pts with active, uncontrolled variceal bleeding or if bleeding recurs despite maximal endoscopic and pharmacologic therapy
Refractory ascites (prolongs survival)
Other: bleeding portal hypertensive gastropathy, bleeding gastric varices, PVT recanalization, Budd-Chiari syndrome, hepatic hydrothorax

Contraindications to TIPS:

Absolute contraindications: - Primary prevention of variceal bleeding, congestive heart failure, severe tricuspid regurgitation, severe pulmonary hypertension, multiple hepatic cysts or masses, Sepsis, unrelieved biliary obstruction

Relative contraindications: - Hepatic encephalopathy, hepatic tumors (especially if centrally located), thrombocytopenia (<20k), moderate pulmonary hypertension

Pre-procedure preparation:

Labs: CBC, CMP, INR
Liver imaging to assess portal system patency and exclude liver masses
Ideally triple phase CT with contrast
In pts with renal impairment or active variceal bleeding, RUQ U/S with doppler is acceptable
TTE to evaluate for evidence of congestive heart failure, pulmonary hypertension, or valvular disease.
Antibiotic ppx with ceftriaxone 1g IV once at the time of TIPS insertion as enteric bacteria within the static portal system can enter systemic circulation
Patients with HE should receive rifaximin prophylaxis starting 2 weeks before procedure and maintained for at least 6 months after the procedure

Management Post-TIPS

Immediately following TIPS, pts are observed in the hospital overnight for complications
Monitor CBC and vitals closely. If hemodynamically unstable, STAT CBC and low threshold to obtain CTA A/P to evaluate for a bleeding source
TIPS causes a substantial increase in venous return to the heart, which can unmask cardiac dysfunction that was previously compensated for
Obtain RUQ U/S with Doppler to assess shunt patency 1 month of TIPS placement, or if ascites and/or variceal hemorrhage reoccur
If patient with a TIPS develops refractory HE, can consider TIPS revision to lessen HE symptoms
Clearance of ascites is not immediate post-TIPS (may take 6-12 weeks), and patients should be maintained on a sodium-restricted diet and diuretics until ascites is adequately controlled.

Hemodynamic Pressure Measurements and Goals:

The HVPG refers to the difference in intravascular pressure between the portal vein and the hepatic vein. During TIPS placement, direct portal pressures are measured and used to calculate the portosystemic pressure gradient (PSPG)
In patients with acute, uncontrolled esophageal variceal bleeding, the desired post-TIPS PSPG is <12 mm Hg or, If the former is not feasible, a reduction ≥50% from baseline PSPG
The desired PSPG for secondary prevention of gastroesophageal variceal bleeding is <12 mm Hg
In patients not achieving a PSPG <12 mm Hg despite dilation of the stent to a maximum 10 mm of diameter, the addition of nonselective beta-blockers (NSBBs) should be considered

Hepatocellular Carcinoma (HCC)

Author: Julie Cui

Background

Fifth most common tumor and the second most common cause of cancer related death worldwide
The incidence in patients with cirrhosis is 2-4% per year
In chronic HBV and NASH, pts can develop HCC without having cirrhosis

Evaluation

Regular screening in pts with cirrhosis (or chronic HBV without cirrhosis) for HCC
RUQ U/S q6mo (with or without AFP)
Routine screening with CT or MRI is not recommended
Options If U/S not satisfactory:
CT A/P w/contrast, in comments specify triple phase for HCC screening
MRI, specify Gadovist (preferred contrast agent)
Contrast-enhanced ultrasound
AFP trend is more useful than one value in time, though AFP >20 should prompt multiphase CT or MRI for further evaluation
Diagnosis can be made either by imaging (most common) or biopsy (rare)
Triple phase CT demonstrates strong early uptake in arterial phase, with subsequent wash-out in portal-venous phase
If diagnosis remains unclear: can surveillance imaging or biopsy
LI-RADS system notes risk of malignancy based on imaging characteristics

LI-RADS Classification:

LI-RADS	What does it mean?	What do we do?
LR-1 to LR-2	Definitely/probably benign	Routine surveillance, consider diagnostic imaging within 6 mos
LR-3 to LR-4	Indeterminate/probably HCC	Repeat or alternative diagnostic imaging in 3-6 mos. Consider Bx for LI-RADS 4
LR-5	Definitely HCC	Plan treatment as noted below
LR-M	Cancer, but may not be HCC

Management

Lesions that meet Milan criteria can qualify for MELD exception points and are considered transplant candidates
This accounts for pts with minimal synthetic dysfunction (and therefore low MELD)

Milan criteria:

Single tumor with diameter >2cm but <5 cm, no more than 3 tumors, each <3 cm
No signs of extra-hepatic involvement or vascular invasion
Liver transplant is definitive treatment, although resection can also be curative (favored in pts with early cirrhosis i.e. Child Pugh A)

Locoregional therapies: Pts with unresectable disease, or who are not surgical candidates

Therapy	Details
Radiofrequency ablation	If in a favorable location and size, IR can percutaneously ablate with a large needle that emits microwave frequencies
Trans-arterial chemoembolization (TACE)	Chemotherapeutic agents injected into the tumor to occlude the feeding artery to the area.
Trans-arterial radioembolization (TARE)	Like TACE, though radioactive compound (i.e. Y-90) is Injected In the the feeding artery
Stereotactic body Radiation Therapy (SBRT)	Radiation therapy: can be used as an alternative to ablation or trans-arterial therapy
Systemic Chemotherapy	For metastatic disease

Coagulopathy in Cirrhosis

Author: John Laurenzano

Background

The liver is responsible for production of both pro- (factor II, V, VII, IV, X, and XI) and anti-coagulants (protein C, S) in hemostasis. Factor VIII is the only one not made by the liver.
Thrombocytopenia is caused by splenic sequestration from portal HTN, failure to produce thrombopoietin (TPO), and bone marrow failure
Hemostatic changes in cirrhotics are incredibly complex, as they involve both procoagulant and anticoagulants. The current thought is that cirrhosis is NO LONGER considered a condition associated with an overall increased bleeding tendency, as the pro-hemostatic and anti-hemostatic pathways are deranged in a way that counterbalance each other.

Evaluation

INR/PT, and PTT are poorly reflective of bleeding risk

Management

Pre-procedural FFP is not recommended, as it has potential harm w/o proven benefit
Low risk procedures (i.e., paracentesis) do not require pre-procedural blood products and per guidelines there is no established INR or platelet cut off
In bleeding pts, the following are recommended per AASLD and AGA guidelines
IV Vitamin K 10mg x 3 days
FFP: Not recommended, unless as part of a balanced transfusion effort to avoid transfusion related coagulopathy, or if a TEG screen suggests potential benefit
Cryoprecipitate: if fibrinogen < 120
Platelets: No specific targets regardless of bleeding. Pre-procedurally, recommend >50
Appropriate DVT ppx should be given with few exceptions (plts <50k, active hemorrhage)

For TEG transfusion recommendations are as follows:

10 mg/kg FFP if R-time >10 minutes
1u Plts if maximum amplitude <55 mm
5u cryo if alpha angle <45

Portal Vein Thrombosis (PVT)

Author: Pakinam Mekki

Background

Portal Vein Thrombosis (PVT) can worsen decompensation (i.e. variceal hemorrhage), however, worsening portal HTN → more sluggish flow → increased risk PVT

Presentation

Often identified asymptomatically on U/S, but can be identified by new or worsening decompensation of portal HTN
Variceal hemorrhage is the most common decompensating event associated with PVT
Intestinal ischemia (abdominal pain, hematochezia) from PVT is exceedingly rare but associated with significant morbidity/mortality

Evaluation

RUQ U/S with doppler
Once identified, should be further assessed with triple phase CT or MRI with Gadovist contrast to exclude HCC with tumor thrombus
Pts with newly identified PVT should undergo EGD to evaluate for high-risk varices, both for diagnostic and therapeutic considerations
PVT in pts without cirrhosis should prompt evaluation for hypercoagulable disorders

Management

Start AC if acute thrombus occludes >50% of main portal vein, <50% but extends into SMV, thrombus is symptomatic, or patient is a transplant candidate (irrespective of size). Requires discussion with attending/transplant team.
AC options: warfarin, LMWH, or DOAC
DOAC's are safe in Childs Class A, can be used with caution in Childs B, and are contraindicated in Childs C
Pts with chronic occlusive PVT (>6 mos) or with cavernous transformation with collaterals do not generally benefit from AC
Pts with high-risk varices should undergo endoscopic management or be on NSBB for prophylaxis for variceal hemorrhage, as noted above
TIPS with portal vein recanalization has recently emerged as a therapeutic modality for PVT in LT candidates to allow for anastomosis, in patient's with chronic PVT and recurrent bleeding/refractory ascites, or in patients whom intestinal ischemia persists despite AC.
Pts should undergo follow up intermittently with US to assess for recanalization. AC may be stopped if there is failure to recanalize.
If pts are not candidates for AC, they'll simply be treated for complications of portal HTN

Alcohol-associated Hepatitis

Author: Ahmad Yanis

Background

Acute onset of rapidly progressive jaundice (within prior 8 weeks) in pt with heavy EtOH intake (>40g in females or >60g in males EtOH/day for >6 mos, or within <60 days of abstinence)
May present after they have quit drinking due to immunosuppressive effects of alcohol
Risk Factors: Female, Hispanic ethnicity, binge drinking, poor nutrition, and obesity

Evaluation

AST >60, AST/ALT >1.5, both values <400 IU/L; TBili >3.0 mg/dL, documentation of heavy EtOH use until 8 weeks prior to presentation (some guidelines state 12 weeks)
Prognostication with Maddrey's Discriminant Function: 4.6 * (PTpt – PTctrl) + Tbili
Maddrey > 32 or MELD > 20 = poor 30d prognosis & may benefit from steroids (see below)
RUQ U/S to rule out obstructive cause of jaundice
Biopsy is not typically required but will show neutrophilic lobular inflammation, hepatocyte ballooning, steatosis, and pericellular fibrosis.
Phosphatidylethanol (PEth) level is a biomarker of ethanol consumption over ~ 4wks; >20 ng/mL can indicate chronic moderate/heavy alcohol intake
A single episode consumption can result in detectable Peth for up to 12 days. Can be elevated for months with regular heavy alcohol intake
EtOH levels may be negative unless acutely intoxicated

Management

Supportive Care is essential! Consult nutrition, start high protein, high calorie diet, high dose Thiamine x 3d, Folate, MVI
Full infection workup (CXR, UA, BCx, paracentesis) regardless of symptoms

Steroids:

Discuss with hepatology team, >20 clinical trials conducted with inconsistent results
Largest trial was the STOP-AH Trial (NEJM 2015) which showed improved mortality at 28 days in post hoc analysis, but not at 90 days in patients with Maddrey > 32.
VA trial (patients with MDF >54) showed increased mortality, indicating a possible ceiling at which point steroids may be harmful.
Individuals with a neutrophil: lymphocyte ratio of 5-8 are most likely to benefit from steroid use.
Treatment dose is prednisolone 40mg daily (preferred over prednisone as it requires hepatic metabolism)
Contraindications to steroids include: presence of infection (must rule out first including TB, active Hep B, sepsis, uncontrolled GI bleeding, AKI w/ Cr >2.5 mg/dL)
The Lille score can be used to assess response to steroids after 7 d of therapy and prognosticate mortality at 6 months
Lille> 0.45 indicates no response to steroids and predicts 75% mortality at 6 months
NAC should be considered as adjunctive therapy to steroids
Monitor on CIWA
Psychiatry consultation as appropriate, consideration of medical therapy (see "Substance Use Disorders" section in psychiatry)

MASH and MASLD

Author: Shabnam Eghbali

Background

Metabolic dysfunction-associated steatotic liver disease (MASLD) presence of hepatic steatosis (>5% of hepatocytes with macro-vesicular steatosis) in the absence of secondary causes (e.g, EtOH or HCV GT3) and at least one of five of the below criteria:
BMI ≥ 25 OR waist circumference > 94 cm (M) / 80 cm (F)
Fasting serum glucose ≥ 100 OR 2-hr post-load glucose levels ≥ 140 OR HgbA1c ≥ 5.7% OR T2DM
Blood pressure ≥ 130/85 OR on anti-hypertensive medication
Plasma triglycerides ≥ 150 OR on lipid lowering treatment
Plasma HDL ≤ 40 (M) / 50 (F) OR on lipid lowering treatment
Metabolic dysfunction-associated steatohepatitis (MASH) evidence of active inflammation and cellular injury +/- fibrosis
Strong association with metabolic syndrome, T2DM, HTN, obesity
Prevalence of MASLD is 25-30% in general population and is now the leading cause of transplantation in American women

Presentation:

MASLD is asymptomatic and frequently found incidentally via imaging
MASH manifests with elevated liver enzymes, typically 2-5x the ULN, in a roughly 1:1 ratio (as opposed to alcoholic steatohepatitis), though ALT may be higher than AST. MASLD or MASH does NOT cause RUQ pain. Patients can still have normal liver enzymes with MASLD or MASH.

Evaluation

Exclusion of alternative causes and comorbid liver conditions: HCV, HBV, EtOH, etc.
Screen for comorbid metabolic disorders: Lipid panel, hemoglobin a1c
Primary risk assessment with FIB-4 (see NITs section)
Diagnosis commonly made via imaging
US is used most frequently, although conventional B mode US lacks sensitivity for lower degrees of steatosis. As a result, controlled attenuation parameter (CAP) on VCTE (Ie FibroScan) is commonly used.
MRI is also acceptable. MRI-proton density fat fraction is a precise method for liver fat quantification (available for clinical care at VUMC)
Liver biopsy should be considered when non-invasive testing suggests significant fibrosis (≥F2)

Management

Aggressive risk factor modification and management of comorbidities (HLD, HTN, T2DM)
Weight loss: Mediterranean diet>low fat diet (dose dependent improvement), increased coffee consumption is associated with less progression of liver disease
MASLD (fat only) Weight Loss Goal: > 5% of body weight
MASH (fat and inflammation) Weight Loss Goal: >10% of body weight
Consider referral to weight loss clinic (BMI >40, or >35 with metabolic comorbidities)
Once the patient is diagnosed with MASLD, evaluation for fibrosis is indicated
Fibrosis-4 (FIB 4) score: First line assessment. Assesses probability of fibrosis.
Elastography: More accurate can be vibration based (fibroscan), US based (sheer-wave), or MR-based. Available at VUMC and can be ordered by anyone. Insurance will not cover MRE if BMI <35
- Fibroscan: <10kPa r/o advanced chronic liver disease (fibrosis); 10-15kPa are suggestive of advanced chronic liver disease; >15kPa are highly suggestive.
Encourage etoh cessation; contributes to fatty liver disease progression
FDA recently approved Rezdiffra (resmetirom) for the treatment of adults with noncirrhotic MASLD with moderate to advanced liver scarring (fibrosis), to be used along with diet and exercise
SGLT2 Inhibitors: May reduce steatosis in patients with MASLD+ DM
Vitamin E: Can improve steatosis and inflammation in the setting of biopsy-proven MASH with evidence of hepatic fibrosis (fibrosis score 2+) in patients w/o DM
GLP-1 agonists: Consider for patients with MASH+DM/obesity as it confers cardiovascular benefit and improves steatosis but probably not fibrosis
GLP-1/GIP agonist (e.g, semaglutide) Tirzepatide): Can reduce steatosis. Can be use in patients with DM or obesity + NAFLD
Metformin, DPP4, statins, and silymarin are well studied in MASH and do not offer meaningful histologic benefit
In the pipeline: FGF21 agonists, THR beta agonists, PPAR agonists

Additional Information

Statins: should be used for HLD in pts with MASH, MASLD, and MASH cirrhosis
Statin use in decompensated MNASH cirrhosis is controversial, and they are less likely to derive benefit given overall poor prognosis, discontinue w/acute on chronic liver failure.

Acute Liver Injury and Failure

Author: Wrinn Alexander

Background

Acute liver injury (ALI): elevated liver enzymes + INR ≥1.5 without encephalopathy
Acute liver failure (ALF): elevated liver enzymes + encephalopathy (any degree of AMS or asterixis) in the absence of pre-existing liver disease*
*Autoimmune hepatitis, HBV, Wilson disease, and Budd-Chiari syndrome can have ALF if they develop new AMS, despite the presence of a pre-existing liver disease
Hyperacute (< 7 d): most often seen with acetaminophen toxicity, Hepatitis A & E, Ischemic; high risk for cerebral edema
Acute (7-21 d): Hepatitis B
Subacute (> 21 d and < 26 wk): most often non-acetaminophen DILI
Alcohol-associated hepatitis (AH) is not ALF (see above)
Duration of <26 weeks is a commonly used cut-off

Etiology

R-factor (if history, exam, and diagnostic data are inconclusive i.e. R-factor is not a replacement to clinical judgement) = (ALT/uln ALT) / (ALP/uln ALP); See chart below - R > 5 = hepatocellular injury; R<2 = cholestatic injury; R 2-5 = mixed injury

Isolated hyperbilirubinemia: Differentiate direct versus indirect - Direct: Refer to cholestatic pattern - Indirect: Gilbert vs. hemolysis

Drugs Associated with liver injury:

Hepatocellular pattern: acarbose, Acetaminophen, Allopurinol, Amiodarone, Baclofen, Bupropion, Fluoxetine, HAART (Nevirapine), Kava kava, Isoniazid, Ketoconazole, Lisinopril, Losartan, Methotrexate, NSAIDs, Omeprazole, Oxacillin/Nafcillin, Paroxetine, Pyrazinamide, Propylthiouracil, Rifampin, Risperidone, Sertraline, Statins, Tetracycline, Trazodone, Valproic Acid
Mixed pattern: Amitriptyline, Azathioprine, Captopril, Carbamazepine, Clindamycin, Cyproheptadine, Enalapril, Flutemide, Nitrofurantoin, Phenobarbital, Phenytoin, Sulfonamides, Trazodone, Verapamil
Cholestatic pattern: Amoxicillin-clavulanic acid, Anabolic steroids, Chlorpromazine, Clopidogrel, Oral contraceptives, Erythromycins, Estrogens, Irbesartan, Mirtazapine, Phenothiazines, Terbinafine, Tricyclics

Hepatocellular Injury: R factor > 5 (Primary elevation of AST/ALT)

Etiology	Description	Work Up
Overdose/Toxins$	Acetaminophen, ASA, alcohol, cocaine, mushrooms (Amanita phalloides)	Acetaminophen, ethanol level, Peth, UDS
Acute Viral Hepatitis	Hep A$, B$, C, D, E; EBV, CMV, HSV, VZV	Viral serologies and PCR
Autoimmune hepatitis*	Presence of circulating autoantibodies and a high serum globulin concentration	Anti-smooth muscle (f-actin), ANA, ANCA, anti-liver kidney microsome (anti-LKM-1), anti-soluble liver antigen/liver-pancreas IgG
Budd-Chiari Syndrome*	Hepatic vein obstruction	Ultrasound of abdomen w/ doppler, CT w/ contrast
DILI – Drug Induced Liver Injury*$	Dose independent (NOT an overdose)	Review patient's med list with NIH Liver Tox Database: https://www.livertox.nih.gov
HELLP Syndrome, Acute Fatty Liver of Pregnancy	HELLP: A severe form of preeclampsia; AFLP: defects in fatty acid metabolism during pregnancy	Check bHCG in females of reproductive age
Ischemic Liver Injury (Shock Liver)$	Shock (can be of any variety)	AST > ALT can be in the thousands, high LDH, history of hypotension, UDS to eval for vasoconstrictive drugs
Wilson's Disease*	Mutation in ATP7B, gene for copper transport protein, leads to accumulation of copper in liver and other organs	Ceruloplasmin level (screening), 24h urine copper (confirmation), quantitative copper on liver biopsy. Genetic testing

*May present with chronic liver injury as well; $May present with AST/ALT >100

Cholestatic Injury: R Factor < 2 (Primarily elevated Alkaline phosphatase)

Etiology	Description	Work Up
Acute biliary obstruction	Choledocholithiasis	Abdominal ultrasound, MRCP, ERCP
DILI – Drug-induced liver injury*$	Dose independent (NOT an overdose)	Review patient's med list. Refer to Liver Tox Database: https://www.livertox.nih.gov Common: Augmentin, Bactrim, amiodarone, Imuran
Malignancy*	Pancreatic malignancy, cholangiocarcinoma	CT abdomen, ERCP
Primary Biliary Cirrhosis*	Autoimmune	AMA, ALP. If AMA + and ALP >225 meets diagnostic criteria. If only one positive, will need liver biopsy.
Primary Sclerosing Cholangitis*	Autoimmune, associated with IBD	MRCP, ERCP
Critical illness or COVID cholangiopathy	Hypotension, COVID	MRCP with biliary stenosis, appropriate history

*May present with chronic liver injury as well; $May present with AST/ALT >100

Evaluation

Neurologic Exam:

See Hepatic Encephalopathy section for grading of HE based on PE/Hx
Grade I and II HE: cerebral edema uncommon
Grade III HE: Cerebral Edema in 25-35% of patients
Grade IV HE: Cerebral Edema in 75% of patients
Signs of increased intracranial pressure:
Pupillary changes, Cushing's triad (HTN, bradycardia, respiratory depression, seizures, increased muscle tone and hyperreflexia, abnormal brainstem reflexes
Consult hepatology once you suspect ALF! (to assist with workup AND for transplant evaluation)

Labs:

CBC w/diff, CMP, Dbili, Mg, Phos, T&S, BCx, UCx, PT/INR, aPTT, fibrinogen
Ferritin, Iron, transferrin (HFE gene mutation testing if Tsat ≥45% and/or elevated ferritin)
Amylase, lipase
Beta-hCG for females of childbearing age; UA to assess for proteinuria if pregnant
ABG with arterial lactate, ammonia (arterial >124 predicts mortality and CNS complications e.g., need for intubation, seizures, cerebral edema, <75 very unlikely to develop ICH)
Viral etiologies: Viral hepatitis serologies (HAV panel, HBV panel, HCV IgG +/- PCR quant, HDV if known HBV (with low or undetectable HBV load) as Misc Reference Test, Hepatitis E PCR sent as miscellaneous if pregnant or travel to southeast Asia), HIV p24 Ag and HIV Ab, EBV Qt, CMV Qt, HSV 1/2, Qt, VZV IgM/IgG
Toxins: UDS, ethanol level +/- Peth, acetaminophen level (drawn ≥4 hours after last known ingestion), salicylate level
Autoimmune/genetic: ANA, ASMA, IgG, AMA (if predominantly elevated ALP), ceruloplasmin, anti-liver/kidney microsomal antibody type 1, anti-liver soluble antigen, alpha-1 antitrypsin
*You may not order all the workup included above; hepatology will guide you on what exactly will need to be ordered.

Imaging:

RUQ U/S with doppler (important to assess vasculature!)
Consider CT with contrast in patients with normal renal function and high suspicion of Budd-Chiari syndrome or malignancy with negative ultrasound (better for assessing the hepatic veins) and helps with transplant evaluation
Consider TTE to assess for cardiac dysfunction and aid in transplantation consideration
Consider CTH or MRI to assess for cerebral edema (findings include decrease in ventricular size, flattening of cerebral convolutions, reduction in signal intensity of brain parenchyma)
Consider ERCP/MRCP for cholestatic etiologies
Discuss possible liver biopsy if etiology unclear
Transjugular approach preferred with clinically demonstrable ascites; a known or suspected hemostatic defect; a small, hard, cirrhotic liver; morbid obesity with a difficult-to-identify flank site; or those in whom free and wedged hepatic vein pressure measurements are additionally being sought.

Management

Any pt with concern for ALF should be cared for in MICU (even if mild change in mental status)
Pts with ALF may die acutely from hypoglycemia, cerebral edema, and infection

ABC's:

Intubate for GCS <8, Grade 3 or 4 HE
IVF resuscitation with isotonic crystalloid (most pts are volume deplete; avoid hypotonic fluids due to risk of cerebral edema)
Vasopressive agents for persistent hypotension (norepinephrine is the preferred agent, addition of vasopressin and stress dose steroids may be warranted)

Monitoring:

Q1-2h neuro checks, Q1-2h glucose checks
Closely monitor CMP, Magnesium, phosphorus, INR q6-8 hrs

Treatment of Primary Injury

Early hepatology consult for liver transplant evaluation and assistance in management
IV N-acetylcysteine: May improve transplant-free survival even in patients WITHOUT non-acetaminophen drug induced acute liver failure
Initial loading dose = 150mg/kg over 1 hour, then 50mg/kg/hr for 4 hours, then 100mg/kg/hr for 16 hours
Patients with early-stage hepatic encephalopathy (grade I/II) have increased transplant free survival, while those with grade III/IV do not

Treatment of Secondary Complications

Infection: Rule out infection with CXR, Blood cultures, UA/UCx for every ALF. Antibiotics only if progressing HE, signs of infection, or development of SIRS
Cerebral edema/increased ICP:
No role for lactulose in the setting of acute liver failure
Grade III-IV hepatic encephalopathy: elevated HOB to 30 degrees, quiet and dimly lit room, should be intubated, avoid sedating medications as feasible, and ICP monitor are recommended (if not feasible, hourly neuro checks can be an alternative). If ICP becomes elevated start targeted therapies to reduce intracranial pressure.
Mannitol or hypertonic saline should be administered for surges of ICP with consideration for short-term hyperventilation
If high ICP is refractory to osmotic agents, consider phenobarbital, indomethacin, and/or cooling to 33-34 degrees Celsius if awaiting LT
Seizures: phenytoin (no evidence to support seizure ppx), short acting benzodiazepines if refractory
Renal Failure: early CRRT if persistent metabolic acidosis, volume overload, falling UOP
Coagulopathy: IV Vit K (at least one dose) routinely to rule out Vit K deficiency, products for invasive procedures or active bleeding only
If trying to differentiate from DIC, can order Factor VIII level (should be normal/high in ALF; low in DIC)
Metabolic: Correction of hypoglycemia (continuous D20) and electrolyte abnormalities
Circulatory dysfunction/shock: Goal MAP >75 mmHg. Ensure intravascularly replete, add norepinephrine first line, vasopressin can be used second line but may increase ICP. Consider stress dose steroids for refractory shock
Additional Supportive Care
PPI for bleeding ppx
Enteral nutrition EARLY; avoid TPN if possible
Prefer propofol for sedation for better neuro exams and may reduce cerebral blood flow

Specific Management by Etiology:

Acetaminophen
Early toxicology consultation if suspected ingestion/overdose
For acute management contact Poison Control 800-222-1222
Activated charcoal within 4 hours of ingestion, most effective within 1 hour
IV N-acetylcysteine per protocol, look up Rumack-Mattew Nomogram and consult with toxicology
- In Epic: search "N-acetylcysteine" and select order set "Acetaminophen overdose"
AFLP/HELLP – delivery
Amanita phalloides – IV fluid resuscitation, PO charcoal, IV penicillin, IV acetylcysteine
Autoimmune – IV steroids following approval by hepatology (and typically post biopsy). Azathioprine generally deferred until cholestasis resolved (Mycophenolate can be used instead)
Budd-Chiari – anticoagulation, IR-guided endovascular therapy, transplant (must rule out underlying malignancy and evaluate for thrombotic disorders)
HAV/HEV – supportive care, consider ribavirin for ALF due to HEV
HBV – nucleos(t)ide analogue; orthotopic liver transplant
HSV – acyclovir, consider administering prophylactically until excluded based on lab work

Criteria for Transplantation:

King's College criteria: helps identify patients needing transplant referral/consideration

A) ALF due to acetaminophen:

Arterial pH <7.3 after resuscitation and >24 hr since ingestion, OR
Arterial lactate >3 after adequate fluid resuscitation, OR
Grade III- IV HE, and SCr >3.4, and INR >6.5 all within 24h period

B) ALF not due to acetaminophen: INR > 6.5 OR 3 of the 5 following criteria:

Etiology: Indeterminate etiology, idiosyncratic drug- induced hepatitis
Age <10 or >40
Interval of jaundice to onset of encephalopathy >7 days
Bilirubin > 17.5mg/dl (300mmol/L)
INR >3.5

Other predictors of poor prognosis in absence of transplant:

Hyperlactatemia: lactate >3.5 after 4 hours of IVF or >3 after 12 hours IVF
Hyperphosphatemia: Phosphate >3.75 at 48-96 hours

Non-Invasive Liver Testing for Liver Disease

Author: Shabnam Eghbali

Evaluation

Who should be evaluated: patients with steatosis noted on imaging or for whom there is a clinical suspicion of MASLD, such as those with metabolic risk factors (e.g., HTN, HLD, T2DM, obesity) or unexplained elevations in liver chemistries
Primary risk assessment for MASLD → FIB-4 – estimates degree of scarring and is based on age, AST, ALT, platelet count; high negative predictive value to exclude advanced fibrosis (F3-4); less reliable in patients under the age of 35 or over the age of 65
If FIB-4 <1.3 → reassess periodically
- Every 1-2 years if T2DM/pre-T2DM or ≥2 metabolic risk factors
- Every 2-3 years if no T2DM and <2 metabolic risk factors
If FIB-4 ≥ 1.3 → secondary risk assessment with elastography Vibration-controlled transient elastography (VCTE) also known as FibroScan if BMI < 35 or MR elastography if BMI > 35)
- Low risk = VCTE <8 kilopascal, MRE without significant fibrosis (F2-4), reassess periodically
- Intermediate/high risk = VCTE >8, MRE F2-4 → referral to Hepatology
If FIB-4 > 2.67 → immediate referral to Hepatology
Secondary risk assessment for MASLD → (VCTE), also known as FibroScan, which provides following measurements:
CAP score (dB/m) → rough estimate of steatosis with relatively limited reliability
- 238 – 260 → S1 (less 1/3 of liver affected by fatty change)
- 260 – 290 → S2 (between 1/3 and 2/3 of liver affected by fatty change)
- 290 – 400 → S3 (mor than 2/3 of liver affected by fatty change)
Liver stiffness (LSM) (kPa) → fibrosis score … ranges differ based on underlying liver disease but approximately,
- 2 – 7 → F0 to F1
- 8 – 11 → F2
- 11 – 14 → F3
- 14 or higher → F4
Limitations to VCTE: not available at all centers, significant central adiposity that interferes with measurements, cardiac device not amenable to use of VCTE
AGILE 3+ – a recently developed score based on combination of AST/ALT ratio, platelet count, diabetes, sex, age, LSM

Shear wave elastography interpretation:

≤ 5 kPa → high probability of being normal
< 9 kPa → In the absence of other known clinical signs, rule out compensated advanced liver disease (cACLD). If there are known clinical signs, may need further test for confirmation
9-13 kPa suggestive of cACLD but need further test for confirmation
13 kPa Rules in cACLD
17 kPa suggestive of clinically significant portal hypertension

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