Cirrhosis and Liver Transplant

Definition

• liver biopsy is not always needed to make the diagnosis of cirrhosis

• diagnosis can be established through clinical, laboratory, and/or imaging findings

  • platelet <160 x 10^3 /uL has a positive likelihood ration of 6.3

• Definitive diagnosis of cirrhosis as well as portal hypertension and etiology

  • trans-jugular liver biopsy with portal pressure measurements

  • will demonstrate presence/lack of cirrhosis and whether portal hypertension is cardiac or liver in origin

  • hepatic venous pressure gradient (HPVG) = wedge pressure - free hepatic pressure

    • HPVG > 5 mmHg = portal hypertension

    • in cardiac hepatopathy there is portal hypertension but HPVG is normal

Signs and Symptoms

• Decompensated cirrhosis, defined by presence of...

  • ascites

    • associated with poor quality of life, increased morbidity/mortality, and poor long term outcomes

    • after first episode of ascites survival is 85% during the first year, 56% at 5y without liver transplant

    • results from increased renal sodium retention due to high activity of the renin-angiotensin-aldosterone system which results from high splanchnic vasodilation and portal hypertension

  • variceal bleeding

    • can occur at an annual rate of ~5-15%

    • most important predictor of bleed is variceal size>decompensated cirrhosis and presence of red wale signs on EGD

  • hepatic encephalopathy

  • jaundice

  • Median survival ~1.5 yr

  • Refer to a transplant center after first episode of decompensation regardless of MELD score given poor survival

• Compensated cirrhosis, does not have any of the above findings

  • median survival ~12 yr

• palmar erythema

• spider angiomata

• thrombocytopenia

  • splenic sequestration

  • reduced activity of hematopoietic growth factor thrombopoietin

  • cirrhotic coagulopathy

  • bone marrow suppression by viral infections or medications

• SBP

  • abdominal pain

  • fever

  • leukocytosis

  • up to 1/3 may be asymptomatic

  • PPI use associated with increased risk of SBP in cirrhotic patients, only use for clear indications

• Portal vein thrombosis

  • may cause portal hypertension with GI bleeding and small bowel ischemia

  • prevalence among cirrhotics is 4.4-15%

  • responsible for ~5-10% of overall cases of portal hypertension

• Sarcopenia

  • negative predictor of outcomes in patient's with cirrhosis

• Hepatopulmonary syndrome

  • occurs in 5-10% of patients awaiting liver transplant

  • those with HPS have higher mortality than those without

  • results from pulmonary vasodilation that leads to gas exchanged abnormalities and hypoxemia

  • presentation varies form mild dyspnea to severe hypoxemia

    • clubbing, cyanosis, and vascular spiders can be seen on exam

  • Diagnosis

    • exclude other causes

    • PaO2 <80 mmHg or Aa gradient >15 mmHg on ABG

    • intrapulmonary vasodilation by contrast echocardiography and/or perfusion lung scanning

      • late bubbles on contrast echocardiography

        • left sided bubbles after the 4th or 5th beat indicative of an intrapulmonary shunt

        • versus: bubbles at the second beat reflect presence of intracardiac shunt

• Portopulmonary Hypertension (POPH)

  • detected in 4-8% of liver transplant candidates

  • results from pulmonary vasoconstrictors that are released from the splanchnic circulation

  • diagnosis made through right heart catheterization

    • pulmonary arterial pressure > 25 mmHg

      • mild POPH with mean pulmonary arterial pressure (MPAP) <35 mmHg is not of major concern

      • moderate (MPAP ≥ 35 mmHg) and severe POPH (MPAP ≥ 45 mmHg) are predictors of increased mortality following liver transplant

        • mortality is 100% with MPAP > 50 mmHg

        • if MPAP can be reduced with vasodilator therapy to < 35 mmHg and pulmonary vascular resistance less than 400 dynes.s.cm-5, transplant is possible

    • pulmonary capillary wedge pressure < 15 mmHg

    • pulmonary vascular resistance > 240 dyenes/s/cm-5

Lab Findings

• Thrombocytopenia

  • moderate = plt < 100 x10^9/L

  • severe = plt <50 x 10^9/L

• Ascites

  • Serum-ascites albumin gradient (SAAG)

    • SAAG >1.1 and ascites total protein <2.5

      • ascites related to cirrhosis

    • SAAG >1.1 and ascites total protein >2.5

      • ascites related to post-sinusoidal hypertension

        • cardiac ascites

        • Budd-Chiari

        • veno-occlusive disease

    • SAAG <1.1 and ascites total protein <2.5

      • Nephrotic syndrome

    • SAAG <1.1 and ascites total protein >2.5

      • tuberculous peritonitis

      • malignant causes

Treatment

• vaccinate against HAV and HBV

• Non-selective beta-blockers are used for primary or secondary prophylaxis of variceal bleed

  • titrate to goal of 50-60 bpm

  • propranolol

  • nadolol

  • carvedilol

    • maximum dose of 12.5 mg daily

      • higher doses are associated with increased side effects and hypotension due to alpha 1 antagonism and excessive first past metabolism

    • more robust effect on reduction of portal pressure than nadolol or propranolol

  • reduce portal pressure, splanchnic blood flow, and gastroesophageal collateral blood flow

    • decrease in hepatic venous pressure gradient >20% is associated with lower rate of first variceal hemorrhage, ascites, and death

    • reduction in cardiac output via β1 thus reducing portal venous inflow

    • reduction in splanchnic vasoconstriction via β2 (the most important effect)

  • has also been shown to reduce gut bacterial translocation

  • avoid in relative hypotension and asthma

• Primary prophylaxis for variceal bleed for patients who have never bled

  • non-selective beta blocker (NSBB)

  • serial variceal band ligation

  • combination of NSBB and band ligation is not recommended given association with more side effects without additional benefit beyond treatment with either therapy alone

• Secondary prophylaxis

  • NSBB + variceal ligation

  • patients who have already bled are at high risk for rebleeding and death

    • median rate of rebleed if untreated is ~60% within the first 1-2 yr

  • Early TIPS evaluation can be considered if

    • there is continued bleeding despite band ligation

    • or at first presentation with Child's C severity (score 10-13) or Child's Class B with active hemorrhage at endoscopy

      • TIPS within 72 hr of EGD following initial vasoactive/endoscopic therapy is associated with improved outcomes

    • Contraindications

      • advanced age

      • HCC

      • heart failure

      • significant hepatic encephalopathy

• Variceal bleeding

  • treat with antibiotics for prophylaxis

    • bacterial infections cirrhotics with upper GI bleed can occur in up to 45% of cases

  • EGD within 12 hr of presentation

  • transfuse for goal hb ~7-8 g/dL

    • overtransfusion or volume overexpansion can precipitate variceal rebleeding

    • restrictive transfusion strategy, holding until Hb is <7 g/dL, leads to improved survival

  • transfuse platelets prior to EGD if plt < 50 x 10^9/L to reduce risk of bleeding during and after procedure

  • octreotide IV

  • Gastric varices

    • tissue adhesive recommended over band ligation because of higher efficacy

    • failure to control bleeding or if there is recurrent bleed from GOV1, TIPS is recommended

• Ascites

  • dietary sodium restriction

  • fluid restriction not required unless there is severe hyponatremia with Na <120-125 mEq/L

  • Spironolactone is more effective than loop diuretics

    • start at dose 50-100 mg daily

    • may cause painful gynecomastia

  • Furosemide

    • start at 20-40 mg daily

    • maintain ratio of 2:5 of furosemide:spironolactone

  • Side effects of diuretics

    • encephalopathy

    • electrolyte abnormalities

  • large volume paracentesis (LVP)

    • when patient's fail diuretics and dietary salt restriction

    • after LVP there is a significant alteration of systemic circulation

      • acute increase of cardiac output

      • reduction in systemic vascular resistance and arterial blood pressure

      • this can be prevented with albumin volume expansion

        • give 8g albumin per L removed

  • TIPS indicated for diuretics intolerance or refractory ascites requiring frequent LVP (> 2x per month)

  • Peritoneal catheter - mainly used in the palliative setting

  • Peritoneovenous shunt

    • a subcutaneously placed silicone tube that transfers ascites from the peritoneal cavity to the systemic circulation

    • can be performed in patients not candidates for TIPS or transplant

    • carries risk of occlusion, infection, and bleeding

  • definitive treatment for refractory cases is liver transplant

• Portal vein thrombosis

  • extent of clot should be assessed with MRI

  • when thrombus involves the main portal vein or is progressing into the mesenteric vein, intestinal ischemia/infarction may occur and anticoagulation should be initiated

  • lovenox and coumadin preferred

  • not enough evidence to support use of DOACs

• Hepatic hydrothorax

  • should NOT be treated with chest tube

    • can lead to hemodynamic, renal, and electrolyte abnormalities

  • oral diuretics and repeated thoracentesis may only be transiently effective with refractory hydrothorax

  • TIPS should be considered in refractory cases

  • definitive treatment for refractory cases is liver transplant

• Spontaneous bacterial peritonitis (SBP)

  • all patients with cirrhosis and ascites who are hospitalized should undergo diagnostic paracentesis

  • Diagnosis with ascites neutrophil count (not total WBC count) >250/mm^3

    • bacteria are isolated from ascitic fluid in only 40-50% of cases

    • SBP is mostly a monobacterial infection

    • patients with SBP are at high risk for developing AKI, which is associated with poor survival

    • treat with IV antibiotics and albumin

      • give albumin 1.5g/kg of body weight on day one and 1 g/kg on day 3

        • reduces incidence of AKI and improves survival in patients with SBP

      • give IV ceftriaxone or cefotaxime

    • probability of SBP recurrence is ~70% at 1 yr

  • Short term antibiotic prophylaxis limited to 7 d in the case of GI bleed

  • Long term antibiotic prophylaxis if...

    • recovered from a prior episode of SBP

      • prophylaxis until ascites resolved

    • ascites total protein <1.5 g/dL and at least one of the following...

      • Child-Pugh ≥9 with serum bilirubin ≥ 3 mg/dL

      • Cr ≥ 1.2 mg/dL

      • BUN ≥ 25 mg/dL

      • Na ≤ 130 mg/dL

  • Risk of C diff colitis with long term antibiotic prophylaxis

  • PPI use associated with increased risk of SBP in cirrhotic patients, only use for clear indications

• Hepatic encephalopathy (HE)

  • usually precipitant-induced in >80% of cases by...

    • dehydration

    • over diuresis

    • infection

    • GI bleed

    • constipation

    • use of narcotics and sedatives

    • may also be caused by PVT, HCC

  • identify and treat precipitant

    • blood ammonia level will not help in the diagnosis or management

  • lactulose

    • titrate to goal 2-3 soft, formed bowel movements per day

    • add rifaximin for recurrent or persistent hepatic encephalopathy

  • zinc can be used if there is documented deficiency (not first line for recurrent HE)

  • L-ornithine L-acetate decreases ammonia levels and improves psychometric testing (not first line for recurrent HE)

• Acute kidney injury (AKI)

  • discontinue diuretics and lactulose

  • obtain cultures and diagnostic paracentesis for SBP

  • May be caused by...

    • pre-renal (albumin responsive) azotemia

    • ATN

    • hepatorenal syndrome (HRS)

  • volume expansion with albumin

  • initiate midodrine and octreotide for HRS if does not improve with trial of albumin and other etiologies are ruled out

• Hepatopulmonary syndrome

  • treatment options are limited

  • MELD exception points granted in advanced cases with PaO2 < 60 mmHg

  • oxygen management after transplant may be challenging but oxygen requirements typically improve slowly after OLT

• HCC

  • determine if falls within Milan criteria

  • presence of portal hypertension (may be suggested by thrombocytopenia in a well compensated cirrhotic) may argue against surgical resection

    • in this case proceed with ablative therapy as a bridge to transplant and to prevent progression of tumor

    • single tumors (<2.5 cm) that are favorably located may be equally well treated by either resection or ablation

Screening

• screen for HCC

  • AFP and abdominal ultrasound every 6 mo

    • if a mass is noted proceed with triple phase CT or MRI to confirm diagnosis

      • enhances on arterial phase and washes out on delayed images with rim visible

    • routine biopsy is not recommended given risk of

      • bleeding

      • tumor seeding

      • possible false negative due to sampling error

• screen for varices

  • EGD at diagnosis of cirrhosis

  • repeat EGD every 2-3 years if there is no evidence of decompensation

  • repeat EGD at first episode of decompensation

Considerations for Liver Transplant

• MELD exception points are given for...

  • HCC

  • hepatopulmonary syndrome

    • qualifies for exception points when paO2 is < 60 mmHg with normal CXR and spirometry

  • portopulmonary hypertension

  • certain inherited and metabolic liver diseases such as

    • hereditary hypercholesterolemia

    • hyperoxaluria

    • familial amyloid polyneuropathy

    • polycystic liver disease

Contraindications to Transplant

• Portopulmonary hypertension

  • mild POPH with mean pulmonary arterial pressure (MPAP) <35 mmHg is not of major concern

  • moderate (MPAP ≥ 35 mmHg) and severe POPH (MPAP ≥ 45 mmHg) are predictors of increased mortality following liver transplant

    • mortality is 100% with MPAP > 50 mmHg

    • if MPAP can be reduced with vasodilator therapy to < 35 mmHg and pulmonary vascular resistance less than 400 dynes.s.cm-5, transplant is possible

• advanced HCC with vascular invasion

• AIDS (not HIV infection) is a contraindication for transplant

Post Transplant Complications

• most common early post-transplant complications

  • acute cellular rejection

  • hepatic artery thrombosis

  • biliary stricture

• Recurrent HCV

  • universal for those transplanted with a detectable viral load prior to transplant

  • clinical course is variable but progression of liver damage and fibrosis appears accelerated

  • treatment post transplant can be curative in up to 96-98% of patients on immunosuppression

  • differentiate recurrent HCV from acute cellular rejection with liver biopsy

    • central endotheliitis is more consistent with acute cellular rejection

    • lobular hepatitis is more consistent with recurrent HCV

• Post-transplant malignancy

  • cumulative incidence of de novo cancer increases form 3-5% at 1-3 yrs to 11-20% at 10 yr post-transplant

  • squamous cell carcinoma and basal cell carcinoma of the skin are the most common form in solid organ transplants

  • cigarette smokers are at increased risk of long cancer and oropharyngeal cancer

  • colon cancer is increased in those undergoing transplant for PSC if they have concomitant IBD

  • risk of prostate cancer does NOT increase after liver transplant

• Pregnancy post-transplant

  • liver transplantation restores sexual function and fertility as early as a few months after transplant

  • pregnancy outcomes for mother an infant post-transplant are generally good, but risk is increased for

    • preterm delivery

    • hypertension/preeclampsia

    • fetal growth restriction

    • gestational diabetes

  • risk of congenital anomalies and live birth rate are comparable to the general population

Treatment

• PCP

  • Bactrim

• CMV

  • valganciclovir

• HSV

  • fluconazole

Treatment

• Tacrolimus

  • 2 mo post-transplant: goal level ~10 ng/mL

  • 8 mo post-transplant: goal level 5-7 ng/mL

• Mycophenolate mofetil

Definition

• liver dysfunction due to insufficient functional liver mass

Signs and Symptoms

• post-operative coagulopathy

Definition

Signs and Symptoms

• severe elevations in AST/ALT

• rising INR

• acidosis

• altered mental status

• hypotension

• unstable

Imaging Findings

• Abdominal Ultrasound with doppler

  • hepatic artery without flow visualized

Treatment

• list for re-transplant as Status 1A (highest priority)

• avoid anticoagulation

  • IV heparin dangerous in the setting of immediate post-transplant status and acutely failing allograft

Definition

• diagnosed on liver biopsy alone

• occurs in 20-30% of transplant recipients

Risk Factors

• under-immunosuppression

  • low tacrolimus level

Pathology Findings

• Major histologic features

  • predominantly lymphocytic

    • mixed inflammatory infiltrate in the portal triad

  • ductilitis

    • destructive or nondestructive nonsuppurative cholangitis involving interlobular bile duct epithelium

  • endotheliits

Treatment

• high dose corticosteroids (first line)

  • >90% of patients respond to this

Definition

Signs and Symptoms

• fever

• leukopenia

• anemia

• secretory diarrhea

• maculopapular rash

Lab Findings

• leukopenia

• anemia

• normla LFTs

  • Versus: acute cellular rejection where LFTs are elevated

Definition

• can result from recurrent episodes of acute cellular rejection or chronic under-immunosuppression

Pathology Findings

• Liver biopsy

  • ductopenia

  • cholestasis

Definition

• HSV

• CMV

Pathology Findings

• multinucleated hepatocytes

• intranuclear inclusions

Lab Findings

• Bilirubin : alkaline phosphatase ration > 2 = suggestive of fulminant Wilson's disease

  • copper level takes too long to result

  • ceruloplasmin is low in half of all patients with acute liver failure regardless of etiology

• High transaminases, low bilirubin = suggestive of acetaminophen toxicity or ischemic injury

• Autoantibodies should be routinely assessed

• serum ammonia < 75 uM = rarely develops intracranial hypertension (ICH)

• arterial ammonia >100 uM on admission = independent risk factor for the development of high-grade hepatic encephalopathy

• arterial ammonia >200 uM predicts ICH

Treatment

• Intracranial Hypertension

  • decrease risk of ICH by giving hypertonic saline to raise serum sodium to 145-155 mEq/L

  • In cases refractory to osmotic agents (e.g., mannitol and hypertonic saline), therapeutic hypothermia (cooling to a core temperature of 32C-34C) may be used to bridge patients to transplantation