Cirrhosis

Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Diagnosis is clinical. Management requires treating the underlying disease, managing complications, and, if required, liver transplantation.

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Epidemiology and Etiology

Epidemiology

  • 8th-leading cause of death in the United States (approximately 50,000 deaths per year)
  • Higher prevalence in non-Hispanic blacks and Mexican Americans
  • A steep increase of death from alcohol-related liver disease has been observed in persons aged 2534 years (> 10% annual increase from 1999–2016).

Etiology

Two most common causes of cirrhosis:

  • Chronic hepatitis C (26%)
  • Alcoholic liver disease (21%)

Overview of potential causes:

  • Alcoholic liver disease
  • Chronic viral hepatitis
    • Hepatitis B
    • Hepatitis C
  • Autoimmune hepatitis
  • Non-alcoholic steatohepatitis
  • Biliary cirrhosis
    • Primary biliary cirrhosis
    • Primary sclerosing cholangitis
    • Autoimmune cholangiopathy
  • Inherited metabolic liver disease
    • Hemochromatosis
    • Wilson’s disease
    • Alpha-1 antitrypsin deficiency
    • Cystic fibrosis
  • Chronic hepatic congestion
    • Cardiac cirrhosis
    • Budd-Chiari syndrome (BCS)
Pathology of alcoholic liver cirrhosis

Cirrhosis due to alcoholic liver disease

Image: “Gross pathology of alcoholic liver cirrhosis” by Centers for Disease Control and Prevention/ Dr. Edwin P. Ewing, Jr. License: CC0 1.0

Pathophysiology

General

Cirrhosis is liver damage that is characterized by diffuse distortion of the basic liver architecture and replacement with scar tissue and regenerative nodules. 

  • Hepatic insult → cytokine release → activation of stellate cells → progressive fibrosis → cirrhosis
  • Stage 1: compensated and asymptomatic
  • Stage 2
    • Decompensated, typically presents with portal hypertension and its possible consequences of ascites and bleeding from esophagogastric varices
    • Loss of hepatocellular function will result in hypoalbuminemia, jaundice, coagulation disorders, and encephalopathy.

Secondary effects

  • Shunting between the portal and systemic circulation → portal hypertension → esophageal varices
  • Impaired liver function causing the decreased synthesis of:
    • Coagulation factors → bleeding
    • Impaired urea metabolism → hyperammonemia → hepatic encephalopathy
    • Albumin → ascites 
    • Transport proteins for hormones: 
      • Increased insulin resistance → diabetes mellitus
      • Impaired metabolism of estrogen and androstenedione (converted to estrogen in adipose cells) → hyperestrogenism

Classification

The Child-Pugh score is used to estimate life expectancy. It serves as the basis for the treatment regimen and transplant eligibility.

Classification1 point2 points3 points
Serum bilirubin (mg/dL)< 2.02.0–3.0> 3.0
Serum albumin (g/dL)> 3.52.8–3.5< 2.8
International normalized ratio (INR)< 1.71.7–2.3> 2.3
Presence of ascitesNoneMildModerate
Hepatic encephalopathyNoneMinimalAdvanced

The sum of the points determines the class and the expected remaining life expectancy:

PointsClassLife expectancy
5–6A15–50 years
7–9B4–14 years
10–15C1–3 years

Clinical Presentation

Nonspecific symptoms

  • The initial stage of cirrhosis is often asymptomatic and most often followed by nonspecific symptoms such as:
    • Fatigue, malaise
    • Weight loss
    • Jaundice (bilirubin deposition)
    • Pruritus (bile salt deposition)
    • Asterixis (due to hepatic encephalopathy)
    • Dupuytren’s contracture
  • Hepatomegaly +/- splenomegaly
  • Ascites (due to portal hypertension and decreased albumin)
  • Skin changes
    • Telangiectasia
    • Caput medusae: periumbilical dilation of subcutaneous veins due to increased portal pressure
    • Peripheral palmar erythema
    • Clubbed nails  
  • Hyperestrogenism
    • Gynecomastia
    • Hypogonadism (testicular atrophy), reduced libido, erectile dysfunction, and infertility
    • Alopecia
  • Amenorrhea
  • Smooth tongue (due to 1 or more nutritional deficiencies (iron, folate, vitamin B12))

Diagnosis

Cirrhosis can be diagnosed via clinical signs, laboratory testing, and ultrasound. The definitive diagnosis and classification is histopathologic (gold standard), which shows fibrosis and replacement of normal liver tissue with collagenous regenerative nodules. However, a biopsy is usually not necessary if the clinical, laboratory, and radiologic data are strongly suggestive of cirrhosis.

Histologic classification

TypeSize of the regenerative nodulesEtiology
Micronodular1–3 mm
  • Chronic viral hepatitis
  • Alcoholic hepatitis
Macronodular (also called post-necrotic cirrhosis> 3 mm
  • Autoimmune hepatitis
  • Wilson’s disease
  • Alpha-1 antitrypsin deficiency

Blood work

A fall in platelet count is the earliest finding, followed many years later by elevations  in INR and bilirubin and a decrease in albumin and glucose levels (pre-terminal events).

Liver function tests

Liver function tests are an unreliable indicator of liver damage. High levels are predictive of liver damage, but low levels don’t rule out liver damage (especially cirrhosis).

  • ↑ AST (aspartate transaminase) and ALT (alanine transaminase) 
  • ↑ Bilirubin 
  • ↑ Gamma‑glutamyl transpeptidase (GGT) 
  • ↑ Alkaline phosphatase (ALP)
  • ↑ Ammonia 
  • ↑ Prothrombin time
  • ↓ Total protein (↓ albumin)

Imaging

  • Ultrasonography (USG): primary imaging modality 
    • Nodular liver surface (regenerative nodules are hypoechoic)
    • Liver is enlarged in the initial stages and atrophic in later stages.
    • Distortion of hepatic architecture viewed as heterogeneous echotexture
    • Atrophic right lobe
    • Doppler may show signs of portal hypertension.
  • Computed tomography (CT):
    • Irregular liver surface due to regenerative nodules
    • Segmental hypertrophy/atrophy
    • Other findings such as varices, nodular liver texture, splenomegaly, ascites

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Management

  • Treat the underlying disorder.
  • Decrease or eliminate any current or potential harm-provoking agents (e.g., alcohol , hepatotoxic drugs) and immunize for hepatitis A and B (if non-immune).
  • Ascites:
    • Salt restriction along with diuretics such as spironolactone and furosemide
    • If refractory ascites develops, it may be drained via paracentesis +/- albumin infusion.
  • Follow the patients for complications (see below).
  • Liver transplantation for patients with alcohol abstinence for > 6 months. MELD-Na (model for end-stage liver disease–sodium) score is used to stratify patients on the transplant list.
    • MELD-Na:
      • Predicts 3-month survival
      • Based on creatinine, INR, total bilirubin, and serum sodium concentration
    • Pathophysiological basis of the MELD-Na score:
      • Elevated creatinine levels: due to decreased renal perfusion associated with hypotension of systemic vasodilatory state 
      • Increased INR: due to decreased synthesis by injured hepatocytes of coagulation factors
      • Elevated bilirubin levels: due to inability of injured hepatocytes to metabolize and/or excrete bilirubin
      • Hyponatremia: a marker of severity of cirrhosis as serum sodium is a reflection of the vasodilatory state seen in cirrhosis
  • Hepatocellular carcinoma (HCC) screening: abdominal urine specific gravity for patients with cirrhosis every 6 months and periodic monitoring of alpha-fetoprotein (AFP)

Complications

Decompensated cirrhosis

  • Portal hypertension
  • Gastroesophageal varices
  • Portal hypertension gastropathy
  • Splenomegaly, hypersplenism
  • Ascites +/- spontaneous bacterial peritonitis (SBP)
  • Worsening of liver function characterized by the presence of severe manifestations:
    • Jaundice
    • Coagulopathy 
    • Hepatic encephalopathy
    • Hepatorenal syndrome
  • Diagnostics:
    • ↑ PT, PTT, and INR
    • ↑ ammonia levels in blood

Variceal bleeds

  • 50% of patients with cirrhosis have gastroesophageal varices
    • One-third of these cause hemorrhage, therefore every patient diagnosed with cirrhosis should receive a screening esophagoduodenoscopy (EGD).
  • Hepatic venous pressure gradient (HVPG) ≥ 10 mm Hg is the strongest predictor of variceal development.
  • Treatment of acute bleeding varices: 
    • IV resuscitation
    • Antibiotic prophylaxis for SBP
    • Vasoactive drugs (e.g., IV octreotide) 
    • Urgent endoscopic interventions: endoscopic band ligation or sclerotherapy
    • TIPS (transjugular intrahepatic portosystemic shunt) may be used for recurrent or refractory varices.
  • Prophylaxis for esophageal varices: propranolol

Hepatorenal syndrome (HRS)

  • Definition: acute kidney injury in patients with acute or chronic liver disease.
  • Pathogenesis: arterial splanchnic vasodilatation induced by nitric oxide and other vasodilators induced by portal hypertension, resulting in hypoperfusion of the kidneys. The patient is oliguric → anuria → progressive kidney failure
  • Type 1: progressive impairment in renal function and a significant reduction in creatinine clearance within 1–2 weeks
  • Type 2: reduction in glomerular filtration rate (GFR) with an elevation of serum creatinine level. Type 2 is fairly stable and associated with a better outcome than that of type 1 HRS.
  • Treatment:
    • Liver transplant is the only curative option in advanced liver disease. 
    • TIPS may be used as bridging therapy.
    • Pharmacotherapy: A combination of midodrine, octreotide, and albumin  increases renal blood flow by raising the mean arterial pressure.

Hepatopulmonary syndrome

  • Definition: hypoxemia that arises from ventilation-perfusion mismatch, intrapulmonary shunting, and limitation of oxygen diffusion
  • Symptoms: dyspnea, platypnea (increase in dyspnea in an upright position, improved by recumbency), and orthodeoxia (desaturation in the upright position, improved by recumbency)
  • Treatment: liver transplant is the only definitive treatment

Hepatic encephalopathy

  • Definition: fluctuations in mental status and cognitive function in the presence of severe liver disease
  • Etiology: Portosystemic shunt around hepatocytes and decreased hepatocellular function cause an increased level of systemic toxins (ammonia) to the brain.
  • Precipitating factors:
    • Nitrogen load (gastrointestinal (GI) bleed, protein load from food intake, renal failure, constipation)
    • Dehydration
    • Drugs (narcotics, central nervous system (CNS) depressants)
    • Electrolyte disturbance (hypokalemia, alkalosis, hypoxia, hypovolemia)
    • Infection (SBP)
    • Deterioration in hepatic function or superimposed liver disease
  • Stages:
    • I: apathy, restlessness, slowed intellect, impaired computational abilities, impaired handwriting
    • II: asterixis, lethargy, drowsiness, disorientation
    • III: stupor (rousable), hyperactive reflexes, extensor plantar response (upgoing Babinski sign)
    • IV: coma (response to painful stimuli only)
  • Diagnostics:
    • Elevated blood ammonia levels 
    • Number connection test: for the assessment of mental status
  • Treatment:
    • First step is to treat the underlying precipitating factor (e.g., dehydration, hypokalemia).
    • Lactulose: converted to lactic acid by intestinal flora → acidification in the gut leads to conversion of ammonia (NH3) to ammonium (NH4+) → ammonium is excreted in the feces and not absorbed via intestine → decreased blood ammonia concentration. Lactulose is titrated to produce 45 bowel movements per day. 
    • Rifaximin: non‑absorbable antibiotic to decrease the intestinal bacterial load

Spontaneous bacterial peritonitis (SBP)

  • Definition: a bacterial infection of ascitic fluid in the absence of other intra-abdominal causes
  • Clinical presentation: 
    • 30% of patients are asymptomatic.
    • Fever, chills
    • Abdominal pain, ileus 
    • Hypotension
    • Worsening encephalopathy 
    • Acute kidney injury (AKI)
  • Diagnostics:
    • Absolute neutrophil count in peritoneal fluid > 250 cells/mm3
    • Since many patients are asymptomatic, do not hesitate to do a diagnostic paracentesis in ascites even in absence of markers of infection.
    • Culture is positive in < 80% of patients (not needed for diagnosis).
  • Treatment:
    • IV cefotaxime or ceftriaxone 
    • IV albumin decreases mortality by lowering the risk of acute renal failure.
  • Prophylaxis: consider in patients with
    • GI bleed: ceftriaxone or norfloxacin once
    • A previous episode of SBP: long-term therapy of norfloxacin or TMP-SMX

Hepatocellular carcinoma

  • Most common type of liver cancer
  • Most common malignant disease associated with cirrhosis
  • Screening: abdominal ultrasound  for patients with cirrhosis every 6 months and periodic monitoring of AFP

Coagulopathy

  • Factor deficiencies: due to inability of damaged  hepatocytes to synthesize most blood coagulation factors (fibrinogen; prothrombin; factor V, VII, IX, X, XI, XII, as well as protein C and S; and antithrombin)
  • Fibrinolysis: due to impaired clearance of tissue plasminogen activator (tPA) and fibrinolytic enzymes, reduced synthesis of a2-antiplasmin and thrombin-activatable fibrinolysis inhibitor, and reabsorption of ascitic fluid into circulation

Hepatic osteodystrophy

  • Definition: structural and metabolic bone changes in patients with chronic liver disease
  • Includes both osteoporosis and osteomalacia
    • Osteoporosis: 
      • Low bone mass due to increased bone resorption and reduced bone formation
      • Causative factors in cirrhosis: alterations in vitamin D and calcium metabolism, vitamin K deficiency, hormonal dysregulation, cytokine release, and deficiency of insulin-like growth factor 1 (IGF-1)
    • Osteomalacia: less common than osteoporosis
      • Decreased bone mineralization of newly formed osteoid
      • Causative factors in cirrhosis: due to negative effects on osteoblast function by: low IGF-1, unconjugated bilirubin, lithocholic acid

Hematologic abnormalities

  • Anemia: 
    • Due partially to decreased erythropoietin synthesis by liver (produced predominantly by the kidney but also by the liver), bone marrow suppression by viral hepatitis, excess alcohol consumption, or medications
    • Hemolysis due to hypersplenism, with destruction of RBCs, having cirrhosis-related altered membranes, within the spleen
  • Thrombocytopenia: due to splenic sequestration, decrease thrombopoietin synthesis  by the liver, and other factors
  • Neutropenia: due to splenic sequestration and other factors, including activated monocytes, proinflammatory cytokines, and endotoxin produced by gut bacteria

Mnemonic

Cirrhosis complications: VARICES

  • V: Varices
  • A: Ascites/Anemia
  • R: Renal failure (hepatorenal syndrome)
  • I: Infection
  • C: Coagulopathy
  • E: Encephalopathy
  • S: Sepsis/SBP

References

  1. Goldberg, E., Chopra, S. Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis. (2018). Uptodate. Retrieved September 15, 2020, from https://www.uptodate.com/contents/cirrhosis-in-adults-etiologies-clinical-manifestations-and-diagnosis
  2. Bacon, B.R. (2018). In Jameson, J.L., et al. (Ed.), Harrison’s Principles of Internal Medicine (20th ed. Vol 2, pp. 2405-2414).
  3. Gill, R.,M., Kakar, S. (2020). Liver and Gallbladder. In Kumar, V., Abbas, A. K., Aster, J.C., (Eds.), Robbins & Cotran Pathologic Basis of Disease. (10 ed. Pp. 828-830). Elsevier, Inc.
  4. Scaglione S, Kliethermes S, Cao G, et al. The Epidemiology of Cirrhosis in the United States: A Population-based Study. J Clin Gastroenterol. 2015;49(8):690‐696. doi:10.1097/MCG.0000000000000208
  5. Elliot B Tapper, Neehar D Parikh. Mortality due to cirrhosis and liver cancer in the United States, 1999-2016: observational study. BMJ, 2018; k2817 DOI: 10.1136/bmj.k2817

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