Liver Pathology

Alcoholic Hepatitis


Jaundice, fever, hepatomegaly, n/v, anorexia, ascites, encephalopathy


  • Labs
    • Transaminases moderately elevated AST 2x ALT. AST>500 or ALT>300 suggest another diagnosis
    • Bilirubin >3
    • INR elevation
    • Hepatitis panel (HAV, HBV, HCV) if no clear hx of alcohol use, autoimmune hepatitis labs (anti-smooth muscle and ANA)
  • RUQ ultrasound- to exclude biliary obstruction/ hepatic vein thrombosis
  • Infectious eval- Sample ascites to look for SBP. Blood cultures for all.
  • Admission alcohol level > 200 is more likely to withdrawal
  • Calculate MELD-Na score to predict 90-day mortality
MELD-Na Calculator



  • Accurate history is key- how much? Pattern of drinking? Hx of withdrawals?
  • Timing
    • 6 hours: withdrawals start
    • 8-12 hours: alcoholic hallucinosis
    • 12-48 hours: seizures
    • 2-4 days: delirium tremens
  • Symptoms of withdrawal: htn, tachy, diaphoresis, low-grade fever, tremor, delirium, seizures etc.
  • Do not over-diagnose alcohol withdrawal:
    • Must distinguish hepatic enecephalopathy from withdrawals. Patients with hepatic encephalopathy have excess GABA stimulation, so GABA stimulating drugs way lead to coma

Alcoholic hepatitis or Cirrhosis?

  • Management is similar, only difference is that you sometimes use steroids in hepatitis


  • Alcohol withdrawals-  phenobarbital (but contraindicated in severe liver disease/ hepatic encephalopathy, benzo (librium), thiamine 500mg IV q8h, nutritional/electrolyte deficiencies (often Mg + Phos, monitor for refeeding syndrome)
  • Phenobarbital- long half life (3-4 days), IV/IM/PO all 100% bioavailability
  • Why phenobarbital may be better than benzos--> Barbiturates have uniform efficacy while benzos sometimes fail to work, benzos may cause paradoxical delirium, barbiturates have more predictable pharmacokinetics, barbiturates are better at preventing seizures
  • Benzos- can start with IV midazolam (short-acting) test dose if alcohol withdrawal dx is unclear
    • IV diazepam is better than IV lorazepam due to faster onset, longer duration of action
    • Lorazepam is better in severe cirrhosis which impairs metabolism of diazepam
  • Glucose monitoring- alcoholics have low glycogen reserves so they're at risk of hypogylcemia
  • Vitamin B1 (thiamine)- prevents Wernicke's encephalopathy
  • Vitamin B6 (pyridoxine)- may be considered for seizures, deficient in alcoholics
  • Steroids: calculate Maddrey's discriminant function, if score>32 then give steroids
Maddrey's Discriminant Function

Maddrey's Discriminant Function


Used to monitor and titrate therapy for alcohol withdrawal. All sections graded on a scale of 0-7. Scores of less than 8-10 indicate minimal to mild withdrawal. Scores of 8 to 15 indicate moderate withdrawal (marked autonomic arousal); and scores of 15+ indicate severe withdrawal (impending delirium tremens).

ComponentScore Range
Paroxysmal Sweats0-7
Tactile Disturbances0-7
Auditory Disturbances0-7
Visual Disturbances0-7
Orientation and Clouding of Sensorium0-4
Total CIWA Score0-67


Chronic liver disease characterized by hepatic fibrosis, distortion of architecture, and nodularity


  • Nonspecific: anorexia, weight loss, fatigue
  • Portal hypertension: ascites, hepatomegaly, variceal bleeding
  • Neurologic: encephalopathy, asterixis
  • Skin: jaundice, palmar erythema, spider angiomas
  • Heme: thrombocytopenia, anemia, coagulopathy
  • Reproductive: testicular atrophy, gynecomastia
  • Poor synthetic function, ↑ ↓ albumin, ↑ INR, ↑ bilirubin


  • RUQ ultrasound
  • Evalute fibrosis: Hepascore and elastography
  • Biopsy (definitive dx, but not always necessary)


  • Treat underlying causes, vaccines, avoid hepatotoxic drugs, monitor for hepatocellular carcinoma (AFP + ultrasound q6 months), liver transplant

Liver Transplant

Considered for end-stage cirrhosis, often decisions are made based on severity of cirrhosis using the Child Pugh Score

Child-Pugh Score for Cirrhosis Mortality


Accumulation of fluid in the peritoneal cavity due to portal hypertension (increased hydrostatic pressure) and hypoalbuminemia (reduced oncotic pressure)

Clinical: Abdominal distension, fluid wave, shifting dullness

Diagnosis: RUQ US, with paracentesis showing SAAG > 1.1


  • Salt restriction (< 2000 mg)
  • Combination Furosemide-Spironolactone therapy
  • For tense ascites: Large volume paracentesis (+ /- supplemental albumin)
  • Refractory: TIPS procedure or transplant

Acute Liver Failure vs. Acute on Chronic Liver Failure

Acute Liver FailureAcute on Chronic Liver Failure
DefinitionSynthetic liver failure (INR > 1.5) with hepatic encephalopathy, No underlying cirrhosis, Hepatic encephalopathy beginning within roughly < 12 weeksNew onset of ascites, hepatic encephalopathy, GI hemorrhage, or hepatorenal syndrome in a patient with cirrhosis, Involves failure of 2+ nonhepatic organs in combination with worsened hepatic function
Signs & SymptomsJaundice, nausea/vomiting, anorexia, Right upper quadrant pain, Pruritus, Distension due to ascites, Increased ICP: hypertension, bradycardia, irregular respirations (Cushing's Triad)-
LabsINR > 1.5, Hyperbilirubinemia, Transaminase elevation, Lactic acidosis, Hypoglycemia, Hyperammonemia (ammonia > 150 associated with increased risk of herniation)-
ImagingThe classic finding is T2/FLAIR hyperintensity with diffusion restriction involving the insular gyri and cingulate gyri-
CausesTylenol, antimicrobials account for 50% (isoniazid, beta-lactams), NSAIDs, statins, stimulants, viral hepatitis, autoimmune hepatitis, Less common causes: Wilson's dx, Budd-Chiari, pregnancy etc.Infection (SBP, urosepsis, pneumonia, and cellulitis), Hemorrhage (variceal bleeding, portal gastropathy, peptic ulceration), Thrombosis (portal vein thrombosis, hepatic vein thrombosis a.k.a. Budd-Chiari syndrome), Hepatic insult, Hemodynamic abnormalities, Iatrogenic
TreatmentDiscontinue Tylenol and other hepatotoxic drugs, Probably discontinue antihypertensives and diuretics, AVOID SEDATIVES, Steroids (if indicated), Antivirals if viral hepatitis, N-acetylcysteine, Target MAP>75, Consider stress-dose steroids, 5% albumin if hypovolemic, Stress ulcer prophylaxis, Lactulose if constipated, Treat electrolyte abnormalities, DVT prophylaxis, D5W/D10W if hypoglycemic, Hyperammonemia- Rifaximin + lactulose OR polyethylene glycolEssentially the same as any other cause of liver failure (albumin, steroids?, midodrine, lactulose, rifaximin, thiamine, B6, empiric antibiotics if GI hemorrhage/infection, DVT prophylaxis +- VitK)

The decision

N-acetylcysteine Dosing

N-acetylcysteine Dosing

Use this calculator to determine the correct N-acetylcysteine (NAC) dose for patients in case of acetaminophen overdose.

Hepatic Encephalopathy

Hepatic encephalopathy due to chronic cirrhosis versus acute hepatic failure must be differentiated. Encephalopathy due to acute hepatic failure is much more serious.

Chronic EncephalopathyAcute Encephalopathy
SymptomsDelirium, stupor, coma, asterixis, hyperreflexia, clonus, respiratory alkalosisFrequently associated with increased ICP and herniation due to cerebral edema
CausesInfection, especially: Spontaneous bacterial peritonitis, Urinary tract infection, Pneumonia, GI bleed, Nonadherence with lactulose or rifaximin (or constipation), Dietary indiscretion with excessive protein intake, Volume depletion (e.g., over-diuresis), Renal failure (including hepatorenal syndrome), Deliriogenic medications (especially opioids or sedatives)Same as chronic, but more often due to acute toxic ingestion
DiagnosisNo definitive test to prove the presence of hepatic encephalopathyAmmonia: Far more useful in acute liver failure than cirrhosis, Imperfect sensitivity (~50-90%), Limited specificity (~75%), Ammonia levels can fluctuate
TreatmentLactulose (30 ml Q2hr until frequent bowel movements, then decrease to 30 ml Q6hr and titrate) OR polyethylene glycol (4 liters over 4 hours). As an osmotic agent, Lactulose helps tx hyponatremia

Rifaximin (550mg PO BID): suppressess ammonia producing bacteria

Empiric thiamine 500mg IV q8h

Surgical: TIPS, ligation of anatomic shunts
All the treatments mentioned in chronic process + focus on increased ICP

Target low-normal pCO2

Target a high-normal sodium level (140-145 mM)

Avoid fever, avoid hypoglycemia (may be especially dangerous in the context of brain injury)

Sedation with propofol (may improve ICP and also prevent seizures)

Avoid hypotension (as this may cause a profound drop in the cerebral perfusion pressure). It might be reasonable to target a somewhat higher MAP than usual to maintain an adequate cerebral perfusion pressure (e.g., >75-80 mm)

Hyperammonemia seems to be the primary driver of elevated intracranial pressure in acute liver failure (continuous renal replacement therapy initiation when ammonia levels are >150 uM/L)

Seizure management, Subclinical seizure is often present in grade III-IV encephalopathy, so there should be a low threshold for obtaining video EEG

Hepatorenal Syndrome


Liver Failure

Systemic Vasodilation (NO Release)

Low SVR + Low BP + Increased CO

Compensatory SNS/RAAS Activation

Failure of Kidneys to Compensate

Persistent Renal Vasoconstriction

Acute Tubular Necrosis (ATN)

Definition: A diagnosis of exclusion

  • Chronic or acute hepatic disease with advanced hepatic failure and portal hypertension
  • AKI: increase in serum creatinine of 0.3 mg/dL/ > 50% within 48 hours OR a rise in serum creatinine to above 1.5 mg/dL
  • Absence of any other apparent cause including shock, nephrotoxic drugs, or ultrasound evidence of parenchymal disease
  • Urine RBC excretion < 50 cells per hpf + protein excretion > 500mg/ day
  • Lack of improvement in kidney function with albumin challenge (IV 1g/kg up ti 100g/day) for 2 days and withdrawal of diuretics

Type 1 vs. Type 2 Hepatorenal Syndrome

  • Type 1 (HRS-AKI): More serious, at least a twofold increase in serum creatinine to a level greater than 2.5 mg/dL in > 2 weeks and urine output less than 400 to 500 mL per day
  • Type 2: Kidney function impairment that is less severe than that observed with HRS-AKI/type 1 disease, ascites refractory to diuretics

Differential Diagnosis

  • NAFLD related causes such as concomitant diabetic nephropathy
  • AKI related to infection (sepsis, SBP)
  • Prerenal azotemia
  • Parenchymal disease (glomerulonephritis)

Distinguishing HRS from other diseases is important for both prognosis and treatment (as many other causes such as prerenal azotemia will improve with fluids, while HRS may worsen with fluids).


  • Renal ultrasound
  • Review of medications for nephrotoxins
  • Urinalysis
  • Evaluation of the hemodynamic status:
    • History is important (e.g., changes in diuretic prescription, lactulose use, oral fluid intake)
    • Bedside evaluation with echocardiography
  • Evaluation for infection (e.g., paracentesis, urinalysis, chest X-ray)
  • POCUS evaluation of hemodynamic status
    • A small and highly collapsible IVC may support a diagnosis of hypovolemia
    • A small IVC without respirophasic variation might suggest the presence of intra-abdominal hypertension
    • Congestive nephropathy may be supported by findings of systemic congestion (e.g., dilation of the IVC)

Urine electrolytes

  • Urine sodium and urinary fractional excretion of sodium (FeNa) are no longer part of the diagnostic criteria for HRS-AKI
  • Fractional excretion of urea (FeUrea) might be more useful


  • HRS-AKI: Median FeUrea ~17
  • Prerenal azotemia: Median FeUrea ~26
  • Acute Tubular Necrosis: Median FeUrea ~44


ICU Management
Norepinephrine continuous IV infusion (0.5 to 3 mg/hr) + Albumin IV bolus (1 g/kg per day [100 g maximum]) + IV Vasopressin starting at 0.01 units/min, titrate as needed
Non-ICU Treatments
1. Terlipressin + Albumin (where available)Terlipressin: IV bolus (1 to 2 mg every 4 to 6 hours)
Albumin: IV bolus (1 g/kg per day [100 g maximum]), followed by 25 to 50 grams per day until terlipressin is discontinued
2. Midodrine + Octreotide + AlbuminMidodrine: 7.5 to 12.5 mg three times daily
Octreotide: IV infusion (50 mcg/hr) or subcutaneous (100 to 200 mcg three times daily)
Albumin: IV bolus (1 g/kg per day [100 g maximum]), followed by 25 to 50 grams per day until midodrine and octreotide therapy is discontinued
Patients Refractory to Initial Therapies
- TIPS: High complication rate and HRS patients are often too ill to undergo
- Hemodialysis or continuous venovenous hemofiltration [CVVH]), when patients are awaiting a liver transplant. Can precipitate cardiac arrest/ death in HRS patients due to hemodynamic instability
Peritoneovenous Shunt: Used very rarely
  • AVOID beta-blockers (nadolol): although they are useful in early cirrhosis for varices, they are contraindicated in HRS and greatly increase mortality


  • The vasoconstrictor terlipressin is used for type 1 hepatorenal syndrome (HRS-1) in many parts of the world and is part of the clinical practice guidelines in Europe
  • 2021- phase 3 trial to confirm the efficacy and safety of terlipressin plus albumin in adults with HRS-1

Results- Verified reversal of HRS was reported in 63 patients (32%) in the terlipressin group and 17 patients (17%) in the placebo group (P=0.006).

Spontaneous Bacterial Peritonitis

Clinical features

  • SBP is often subtle (for example, 13% of patients are asymptomatic)
  • Fever or hypothermia.
  • Nausea/vomiting, ileus, and/or diarrhea.
  • Abdominal pain occurs in about half of patients. However, SBP usually doesn't cause frank peritoneal signs or focal pain (if these are present, then secondary bacterial peritonitis should be suspected)
  • Can trigger failure of other organs. In many cases, these other organ failures are more obvious than SBP itself
    • Hepatorenal syndrome
    • Hepatic encephalopathy
    • Gastrointestinal hemorrhage
    • Septic shock
  • Acute-on-chronic liver failure (ACLF)


  • Indications
    • Upon hospital admission: Any patient with cirrhosis and ascites.
      • SBP is present in ~10% of patients admitted to the hospital with cirrhotic ascites, so it should be suspected in any cirrhotic patient who is admitted to the hospital even in the absence of symptoms
      • This includes admission for GI bleed
    • After hospital admission: For patients with cirrhosis and ascites who deteriorate in the hospital, with clinical features concerning for SBP, including:
      • Fever, hypothermia, and/or septic shock
      • Worsening gastrointestinal symptoms (e.g., nausea, emesis, ileus, abdominal pain)
      • Worsening hepatorenal syndrome and/or hepatic encephalopathy
  • Tips on diagnostic paracentesis
    • There is no need to correct the INR (in cirrhosis, the INR doesn't predict bleeding)
  • Consider using a very thin lumbar puncture needle
  • Before needle insertion, look with ultrasonography:
    • (a) Confirm that there is a sizable pocket of fluid.
    • (b) Measure the thickness of the abdominal wall.
    • (c) Use Doppler to exclude the presence of any arteries running through the abdominal wall
  • Ascitic fluid labs to obtain
    • Cell count & differential
    • Gram stain
    • Bacterial cultures
    • Total protein, albumin
    • Glucose
    • Lactate dehydrogenase

Serum Ascites Albumin Gradient

Primary vs. Secondary Bacterial Peritonitis

CriteriaPrimary Bacterial PeritonitisSecondary Bacterial Peritonitis
DefinitionBacterial infection of the peritoneal cavity without an identifiable intra-abdominal sourceBacterial infection of the peritoneal cavity resulting from an intra-abdominal source such as organ perforation or inflammation
Translocation mechanismSingle bacterium translocating into ascitesPerforation or inflammation of an intra-abdominal organ
CommonalityMore commonLess common
Response to medical therapyGenerally responds to medical therapyMay often fail to respond to antibiotics alone
PresentationNo frank peritoneal signs or localizing abdominal painMay have frank peritoneal signs or localizing abdominal pain
Ultrasonography findingsAscitic fluid without septations or debrisComplex, loculated fluid with septations and debris
Microbiology findingsSingle bacterium on gram stain or cultureMultiple different organisms on gram stain or culture
Laboratory criteriaUsually not metAt least two of the following criteria are present in ascitic fluid: Total protein >1 g/dL, Glucose <50 mg/dL (2.8 mM), Lactate dehydrogenase above the upper limit of normal for serum (~225 U/ml)
Diagnostic imagingCT scan of abdomen/pelvisCT scan of abdomen/pelvis and/or right upper quadrant ultrasonography if biliary pathology is suspected


  • Three criteria are required:
    • (1) Chronic underlying cirrhosis
    • (2) Ascites neutrophil count >250/mm3
    • (3) Exclusion of secondary bacterial peritonitis
  • Ascitic fluid cultures are often negative, so SBP may be diagnosed without microbiological proof of infection.


  1. Antibiotics
    • Initiate empiric antibiotic therapy as soon as ascitic fluid demonstrates SBP
    • For community-acquired SBP, use a third-generation cephalosporin such as ceftriaxone. Consider broader coverage for septic shock or multi-organ failure.
    • For nosocomial SBP, use broader coverage antibiotics based on the hospital's antibiogram and the presence of drug-resistant organisms
    • Narrow antibiotics based on ascitic fluid cultures, targeting the identified organism
    • Duration of antibiotic therapy is typically 5-7 days
  2. Albumin
    • Administer 1.5 gram/kg of 20% albumin at the time of diagnosis, followed by 1 gram/kg 48 hours later
    • Albumin reduces the incidence of hepatorenal syndrome and mortality
    • The benefit of albumin has been demonstrated regardless of disease severity, and it is not recommended to omit albumin based on low-risk criteria
  3. Evaluate Antihypertensives and Nephrotoxic Medications
    • Discontinue beta-blockers as they may increase the risk of hypotension and hepatorenal syndrome
    • Consider holding other antihypertensives or vasodilators, especially ACE inhibitors or ARBs
    • Discontinue or avoid nephrotoxic medications
  4. Repeat Paracentesis after 48 hours
    • Guidelines recommend repeating a paracentesis after 48 hours
    • Repeat paracentesis may be unnecessary if a single susceptible organism is isolated, the patient is improving clinically, and there is no suspicion of secondary bacterial peritonitis
    • Re-culturing can help identify bacterial resistance
    • Lack of at least 25% decrease in neutrophil count suggests treatment failure. Consider a CT scan to evaluate for secondary bacterial peritonitis
    • Escalation to broader antibiotics may be necessary