Cirrhosis

Cirrhosis is a condition caused by chronic damage to the liver, most commonly due to excessive alcohol consumption, nonalcoholic fatty liver disease, or hepatitis C. Other causes include inflammatory or metabolic diseases, such as primary biliary cirrhosis and hemochromatosis. Cirrhosis is characterized by hepatic parenchymal necrosis and an inflammatory response to the underlying cause. Subsequent hepatic repair mechanisms lead to fibrosis and abnormal tissue architecture, which impair liver function. Patients can present with a range of symptoms, including ascites; hepatosplenomegaly; and skin manifestations of cirrhosis, such as jaundice, spider angioma, and/or palmar erythema. Men may also display signs of feminization (e.g., gynecomastia, hypogonadism). In severe cases, the accumulation of toxic metabolites or involvement of additional organs can lead to complications such as hepatic encephalopathy and hepatorenal syndrome (HRS). Laboratory studies show signs of hepatocyte damage (e.g., elevated liver enzymes, hyperbilirubinemia) and/or impaired hepatic synthetic function (e.g., prolonged prothrombin time, low albumin). Abdominal ultrasound typically shows shrunken, heterogeneous liver parenchyma with a nodular surface. A biopsy is the method of choice for confirming the diagnosis; however, it is usually only performed if the results from other diagnostic modalities are inconclusive. Management consists of treatment of the underlying disease (e.g., avoidance of toxic substances, antiviral drugs), adequate calorie intake, and medication for treating complications (e.g., spironolactone for ascites). In cases of decompensated cirrhosis, interventional procedures may be used to alleviate symptoms (e.g., paracentesis to drain ascites) or as a bridge until liver transplantation is possible.

• Prevalence: approx. 0.27% in US adults ^[1]
• Sex: ♂ > ♀ (2:1) ^[2]
• Mortality ^[2]
  • Responsible for approx. 1–2% of all deaths in the US (12^th leading cause of death)
  • Most deaths occur in the fifth to sixth decade of life.

Epidemiological data refers to the US, unless otherwise specified.

• Hepatotoxicity
  • Long-standing alcohol use disorder (one of the two most common causes of chronic liver disease in the US)
  • Medications; (e.g., acetaminophen, amiodarone, chemotherapy drugs such as methotrexate)
  • Ingestion of aflatoxin (produced by Aspergillus) ^[3]
  • Industrial chemicals such as tetrachloromethane and various pesticides
• Inflammation
  • Chronic viral hepatitis: hepatitis B, hepatitis D, and hepatitis C (most common cause of cirrhosis in the United States)
  • Primary biliary cholangitis
  • Primary sclerosing cholangitis
  • Autoimmune hepatitis
  • Parasitic infections (e.g., schistosomiasis, leishmaniasis, malaria)
  • IgG4 cholangiopathy
• Metabolic disorders
  • Nonalcoholic steatohepatitis; (NASH)
  • Hemochromatosis
  • Wilson disease
  • α1-antitrypsin deficiency
  • Porphyrias
  • Glycogen storage disease
  • Cystic fibrosis
  • Hereditary fructose intolerance
• Hepatic vein congestion or vascular anomalies
  • Budd-Chiari syndrome
  • Cardiac cirrhosis (congestive hepatopathy)
  • Osler-Weber-Rendu syndrome ^[4]
• Cryptogenic cirrhosis: cirrhosis of uncertain etiology despite adequate diagnostical efforts

Cryptogenic cirrhosis is a diagnosis of exclusion and should only be considered after a complete patient evaluation has ruled out all other possible causes of cirrhosis.

Hepatitis C, alcoholic liver disease, and NASH are the most common causes of cirrhosis in the US.

• Cirrhosis is characterized by irreversible diffuse fibrosis of the liver (the final common pathway for chronic liver diseases).
• Pathogenesis is multifactorial.
  • Different liver cells and cytokines are involved in the activation and progression of liver fibrosis.
  • Cytokine‑mediated activation of hepatic stellate cells has been identified as a central element for developing fibrosis.
• The following three mechanisms have been described for all types of liver cirrhosis: ^[5]
  1. Degeneration and necrosis of hepatocytes
     • Activated Kupffer cells destroy hepatocytes, activate hepatic stellate cells, and promote inflammation.
     • Inflammatory cytokines (e.g., TGF-β, PDGF) → hepatocyte apoptosis and hepatic stellate cell activation → excess collagen production
  2. Fibrotic tissue and regenerative nodules replace the liver parenchyma
     • Hepatocyte destruction triggers repair mechanisms → excess formation of connective tissue (fibrosis)
     • Excessive connective tissue in periportal zone and centrilobular zone → regenerative nodules and fibrous septa → compression of hepatic sinusoids and venules → ↑ portal vein hydrostatic pressure → intrasinusoidal hypertension → ↓ functional sinusoids
  3. Loss of liver function: sinusoidal capillarization → loss of fenestration and scar tissue formation→ impaired substrate exchange → loss of normal liver function (exocrine and metabolic)

Patients with cirrhosis can be asymptomatic (compensated cirrhosis). Disease progression leads to fatigue, weight loss, abdominal distention, and spider angiomata followed by decompensated cirrhosis, manifesting with bleeding varices, ascites, encephalopathy, and jaundice.

Nonspecific features

• Patients are often initially asymptomatic.
• Fatigue, malaise, anorexia, and weight loss

Specific features

Dermal features

• Pruritus
• Jaundice
• Telangiectasia: most commonly spider angiomata (a central red arteriole with numerous, thin arterial extensions, commonly manifesting on light, sun-exposed skin and the trunk)
• Caput medusae
• Palmar erythema (plantar erythema also possible) ^[6]
• Nail clubbing
• Petechiae and purpura
• Generally dry and atrophic skin
• White nails with ground-glass opacity (also known as “Terry nails”)
• Lacquered lips, smooth red tongue

Abdominal features

• Nausea, vomiting
• Hepatomegaly (possibly causing dull RUQ pain)
• Splenomegaly
• Ascites

Hormonal disorders

• Hyperestrogenism ^[7]
  • Changes in the hepatic metabolization of sex hormones cause an imbalance in the estrogen-androgen ratio, resulting in a marked increase in systemic estrogen levels.
  • In men, increased estrogen levels cause feminization.
    • Gynecomastia
    • Hypogonadism; (e.g., testicular atrophy, reduced libido, erectile dysfunction, infertility)
    • Decreased body hair (e.g., loss of chest hair, a female pattern of pubic hair distribution)
  • In women, a massive increase in estrogen can cause amenorrhea.

Other

• Asterixis
• Fetor hepaticus: bad breath with a characteristic sweet, pungent smell caused by an accumulation of dimethyl sulfide
• Dupuytren contracture
• Peripheral edema ^[8]
• See also “Clinical features” in “Portal hypertension.”

Specific clinical features due to rare causes

• Hemochromatosis: dark, bronze skin color, and diabetes (bronze diabetes)
• Wilson disease
  • Neurological/psychiatric symptoms (parkinsonism and personality changes)
  • Indirect hyperbilirubinemia due to hemolysis.
• Alpha‑1 antitrypsin deficiency: lung emphysema (typically before 50 years of age) ^[9]

General principles ^[10][11]

• Diagnosis is typically based on a combination of typical clinical features, laboratory findings, and features on imaging but liver biopsy is the gold standard.
• Initial evaluation:
  • Comprehensive history and clinical examination
  • Routine laboratory studies and screening for the underlying etiology (e.g., viral hepatitis panel)
  • Abdominal ultrasound to evaluate the liver parenchyma and detect complications
• Additional evaluation (e.g., biopsy) may be needed to stage fibrosis or if the etiology remains unclear
• Periodically evaluate for complications (e.g., HCC, esophageal varices).

Patients with cirrhosis are usually either asymptomatic with incidental abnormal findings on laboratory studies or imaging, or present late with features of decompensated cirrhosis.

Laboratory studies

Routine laboratory studies ^[10][12][13]

• Liver chemistries
  • Transaminases: ↑ ALT and AST
    • ALT > AST: present in most liver diseases (e.g., NAFLD, viral hepatitis)
    • AST > ALT: indicative of alcoholic liver disease and/or cirrhosis of any etiology
    • Massive AST and/or ALT elevation (> 15 times ULN): Consider differential diagnoses (e.g., acetaminophen toxicity, acute viral hepatitis, autoimmune hepatitis).
  • ↑ Bilirubin (may be normal initially)
  • ↑ ALP
  • ↑ Gamma‑glutamyl transferase (GGT)
• Coagulation studies: ↑ prothrombin time (↑ INR) because of decreased production of coagulation factors
• CBC
  • Thrombocytopenia: due to decreased thrombopoietin production by the liver and/or splenomegaly ^[12]
  • Anemia: multiple potential causes, e.g., vitamin B₁₂ or folic acid deficiency , chronic blood loss, splenic sequestration
  • Leukopenia
• CMP
  • ↓ Albumin
  • ↓ Total protein
  • Hyponatremia

Liver chemistries may be normal in early compensated cirrhosis. ^[10]

Some CBC abnormalities are due to the combination of increased hepatic and splenic sequestration of thrombocytes (portal hypertension leads to splenomegaly with hypersplenism) and decreased production of hematopoietic factors by the liver.

Hepatocyte injury: ↑ AST, ALT, ALP, GGT. Synthetic dysfunction: ↑ bilirubin and PT/INR; ↓ albumin and platelets

Additional laboratory studies ^{[10][13][14][15]}

These studies may help to identify the underlying etiology and further evaluate liver function. Modification may be required based on clinical features and the presence of risk factors.

• Viral hepatitis: especially in patients with risk factors
  • Hepatitis B and hepatitis C: HBsAg, IgM anti-HBc, anti-HCV
  • Hepatitis A and hepatitis E: IgM HAV, IgM HEV
• NASH: fasting lipid levels and HbA1c
• Hemochromatosis: serum iron, ferritin, transferrin saturation
• Alcoholic liver disease: assess for alcohol use disorder; consider measuring alcohol biomarkers.
• Autoimmune hepatitis: total IgG or serum electrophoresis (showing hypergammaglobulinemia), ANA, ASMA, anti-LKM-1 antibody, anti-soluble liver antigen antibody
• Alpha-1 antitrypsin deficiency: alpha-1 antitrypsin level and phenotype
• Wilson disease: serum ceruloplasmin, serum total and free copper, urinary copper
• Primary biliary cholangitis: antimitochondrial antibodies (AMA or AMA-M2), ALP, bilirubin
• Primary sclerosing cholangitis: cholestasis parameters (GGT, ALP, and bilirubin), pANCA, IgG
• Other tests ^[16][17]
  • Ammonia (not routinely indicated) ^[17]
  • Plasma cholinesterase
  • Serum protein electrophoresis: ↓ albumin band, ↑ gamma band, and unchanged alpha‑1, alpha‑2, and beta globulin fractions ^[16]

Imaging

Abdominal ultrasound with Doppler ^[10][18]

• Indications
  • Suspected cirrhosis: best initial test
  • Established cirrhosis: for HCC screening and detecting complications
• Findings
  • Liver form and structure
    • Nodular liver surface
    • Atrophy of the right lobe
    • Loss of structural homogeneity (hyperechoic or variable increase in echogenicity) with fibrous septa
  • Liver size
    • Initially enlarged ^[19]
    • Atrophies and shrinks with disease progression ^[19]
    • Hypertrophy of the caudate lobe and left lobe ^[18][20]
    • Atrophy of segment IV
  • Other possible findings
    • Changes in liver vasculature
    • Complications of portal hypertension: ascites, splenomegaly, portal vein thrombosis (PVT), increased portosystemic collateral flow ^[19]

CT abdomen ^[18][21]

• Indication: patients in whom adequate assessment with ultrasound is not possible (e.g., because of obesity)
• Findings: similar to those on ultrasound
  • Relative hypertrophy of the left lobe and caudate lobe
  • Regenerative nodules
  • Irregular liver surface
  • Indirect findings: ascites, splenomegaly, portosystemic collaterals

Liver biopsy ^[10][13]

• Indications
  • In cases of diagnostic uncertainty (gold standard)
  • Grading and staging of inflammation and fibrosis (e.g., using the IASL score or METAVIR score)
  • Monitoring treatment response (e.g., in autoimmune hepatitis)
  • Evaluation of focal lesions
• Findings: See “Pathology.”

Screening for complications

• Screening for esophageal varices: EGD at time of diagnosis and every 1–3 years depending on the presence and size of the varices on initial screening ^[10]
• HCC screening: abdominal ultrasound every 6 months ^[10][22]

Advanced testing

Noninvasive liver fibrosis scoring systems ^[10][23]

These biomarker-based tools can be used as an adjunct to confirm and stage cirrhosis of certain etiologies.

• AST-to-platelet ratio index (APRI)
  • Used for cirrhosis caused by HCV or HBV
  • An APRI > 1 is suggestive of cirrhosis.
• Fibrosis-4 score
  • Used for cirrhosis caused by HCV, HBV, or NAFLD
  • Parameters: age, platelets, AST and ALT levels
  • Score < 1.45: advanced fibrosis unlikely ^[24]
• NAFLD fibrosis score
  • Parameters: age, BMI, AST, ALT, glucose, platelets, albumin
  • A score > 0.676 is predictive of advanced fibrosis in NAFLD.

Liver elastography ^[10][25][26]

• Definition: a technique that measures liver stiffness to help determine the degree of fibrosis
• Indication: diagnosis and staging of liver fibrosis and cirrhosis
• Modalities
  • Transient elastography (most common): uses a device (FibroScan®) that only performs elastography; no direct visualization of the liver
  • Acoustic radiation force impulse: It is integrated into a conventional ultrasound system, enabling simultaneous elastography and visualization of the liver. ^[27]
  • Other: magnetic resonance elastography, strain elastography

Model for end-stage liver disease score (MELD score) ^[28]

• Used to predict the three-month mortality rate of patients with cirrhosis
• Primarily used to prioritize patients for liver transplantation ^[28]
• Patients are given a score from 6 to 40 based on serum bilirubin, INR, and creatinine levels.
• Patients with high scores have the worst prognosis without intervention and should therefore be prioritized for transplantation (if appropriate)

Child-Pugh score ^[22]

• A prognostic grading scale that assesses survival rate and predicts the likelihood of developing complications based on bilirubin and albumin levels, prothrombin time, and the presence of ascites and encephalopathy
• Can be used as a prognostic scoring system ^[29]
  • Child‑Pugh class A: one-year survival rate of ∼ 100%
  • Child‑Pugh class B: one-year survival rate of ∼ 80%
  • Child‑Pugh class C: one-year survival rate of ∼ 45%

CHILD's ABCDEs: Albumin, Bilirubin, Coagulation (i.e., ↑ INR), Distended abdomen (i.e., ascites), and Encephalopathy

General principles ^[10][30]

Patients with cirrhosis are typically managed in consultation with specialists.

• Treat the underlying condition (e.g., antivirals for HCV); see “Etiology.”
• Screen for, recognize, and treat complications and decompensations (see “Complications of cirrhosis”).
• Provide supportive care to:
  • Avoid further liver damage
  • Potentially reverse fibrosis or early cirrhosis
• Conduct regular staging of cirrhosis (see “Staging of cirrhosis”)
• Consider workup for liver transplantation, depending on stage and etiology.

Supportive care ^{[10][30][31][32]}

• Avoid hepatotoxic substances.
  • Alcohol
    • Complete abstinence is recommended for patients with cirrhosis.
    • Initiate treatment for alcohol disorder if present.
  • Typical drugs to avoid include: ^[30]
    • NSAIDs
    • Opiates
    • Benzodiazepines in hepatic encephalopathy
  • Stop nonessential medications. ^[30]
• Prophylaxis
  • Nonselective beta blockers (e.g., propranolol) may be indicated for prophylaxis of esophageal varices and to prevent variceal bleeding
  • Routine vaccinations: pneumococcal (PPSV23), hepatitis A, hepatitis B, influenza, SARS-CoV-2, and tetanus ^[10]
  • Avoidance of raw seafood and unpasteurized dairy ^[10]
  • Prophylactic antibiotics (e.g., after previous spontaneous bacterial peritonitis or GI bleeding)
• Nutrition: Aim for a balanced diet with adequate calorie intake. ^[30]
  • Protein intake: Aim for 1.0–1.5 g of protein per kilogram of dry body weight per day; protein restriction is no longer recommended. ^[30]
  • Fluid restriction: if serum sodium level is < 120 mmol/L ^[30]
  • Sodium restriction: a crucial component of ascites management ^[10][30][31]

Liver transplant ^[33]

• A liver transplant is the only curative option in patients with cirrhosis.
• Indications for liver transplant evaluation include:
  • Occurrence of an index complication: i.e., ascites, hepatic encephalopathy, variceal hemorrhage
  • Hepatocellular dysfunction resulting in a MELD score of ≥ 15

• Fibrosis (fibrous septa)
• Replacement of normal liver tissue with collagenous regenerative nodules (histological staging is based on the size of the regenerative nodules) ^[34]
• Abnormal cell activation with infiltration of inflammatory cells
• Loss of physiological vessel architecture (central vein disappearance)

• See “Alcoholic liver disease,” “Hepatitis B,” and “Hepatitis C” for specific pathological findings related to these conditions.

Overview ^[35]

Cirrhosis-associated ascites and edema and elevated bleeding risk increase the risk for hypovolemic shock.

Vitamin K infusion may improve clotting function in select patients with vitamin K deficiency; it is unlikely to be effective in patients with advanced liver disease and coagulopathy.

We list the most important complications. The selection is not exhaustive.

• Definition: the development of ascites, hepatic encephalopathy, or GI bleeding in patients with cirrhosis ^[35]
• Onset: can be triggered by an acute event (e.g., bleeding, sepsis) or develop gradually (e.g., ascites, encephalopathy) ^[38][39]
• Common precipitating factors^[39]
  • Infection (e.g., spontaneous bacterial peritonitis) or sepsis
  • Alcohol consumption
  • Medications (e.g., NSAIDs)
  • GI bleeding
  • Dehydration
  • Constipation
  • Acute PVT
  • HCC
• Diagnostics: to establish the cause of decompensation
  • CBC, BMP, liver chemistries
  • Magnesium and phosphate levels
  • Coagulation panel
  • Consider type and screen.
  • Paracentesis in patients with ascites
  • CRP, blood cultures, urinalysis and culture, chest x-ray
  • Abdominal ultrasound to assess for PVT
• Acute management: See “Management of acute liver failure.” ^[31][39][40]
  • Gastroenterology consult
  • Treat the underlying cause and complications (if applicable).
• Prognosis: In patients with decompensated cirrhosis, survival rates are usually poor unless liver transplantation is performed.

Hepatopulmonary syndrome

Definition

A condition characterized by hypoxemia, intrapulmonary vasodilatation, and portal hypertension in the presence of cirrhosis

Pathophysiology

• Not completely understood
• Portal hypertension and liver damage → translocation of bacterial endotoxins → changes in the production of cytokines and pulmonary vasodilators → ↑ nitric oxide in the lung vessels → pulmonary vasodilation → hepatopulmonary syndrome

Clinical features ^[41]

• Dyspnea
• Platypnea
• Orthodeoxia

Diagnostics ^[41]

• Diagnostic criteria: All criteria must be fulfilled.
  • Presence of liver disease
  • Intrapulmonary vascular dilatation detected on contrast echocardiography
  • Abnormal arterial oxygenation confirmed by elevated A-a gradient
• Pulse oximetry: (screening test): Hypoxemia
• Imaging
  • Contrast echocardiogram (gold standard)
  • Lung perfusion scintigraphy (Tc-99m macroaggregated albumin): helps diagnose and quantify intrapulmonary vasodilation

Treatment ^[31][41]

• Supportive management
  • Supplemental oxygen to maintain O₂ saturation > 88%
  • Pulse oximetry monitoring
• Definitive treatment: liver transplantation ^[31]

Portopulmonary hypertension (POPH) ^[41]

Definition ^[41]

Portopulmonary hypertension is a diagnosis of exclusion made in patients with pulmonary arterial hypertension and portal hypertension after other causes have been ruled out.

Pathophysiology

• Not completely understood
• High cardiac output in advanced liver disease → wall shear stress in pulmonary vasculature → ↑ vasoactive and angiogenic substances (e.g., endothelin-1) → hypertrophy of smooth muscle cells and fibroblasts, fibrosis of intimal sheath, and microaneurysms of pulmonary arterioles

Clinical features ^[31][41]

• May be asymptomatic
• Features of pulmonary hypertension
• Features of right heart failure

Risk factors ^[41]

• Female sex
• Autoimmune liver disease

Diagnostics ^[41]

• Transthoracic Doppler echocardiography (initial): Typical findings include right ventricular hypertrophy or dysfunction, and increased right ventricular systolic pressure.
• Right heart catheterization (gold standard) ^[41]
  • Typical findings include:
    • ↑ Mean pulmonary artery pressure (mPAP)
    • ↑ Pulmonary vascular resistance (PVR)
    • Normal pulmonary artery wedge pressure (PAWP)
  • Severity of POPH
    • Mild: mPAP < 35 mm Hg
    • Moderate: mPAP 35–44 mm Hg
    • Severe: mPAP ≥ 45 mm Hg
• Diagnostic criteria: All criteria must be fulfilled.
  • Clinical features of portal hypertension or elevated portal venous pressure
  • mPAP > 25 mm Hg
  • PVR > 3 Wood units
  • PAWP < 15 mm Hg

Congestive heart failure and severe POPH (mPAP ≥ 45 mm Hg) are absolute contraindications to elective TIPS. ^[41]

Treatment ^[31][41]

• Pharmacotherapy
  • Drugs used in primary pulmonary arterial hypertension (e.g., epoprostenol, bosentan, or sildenafil) may be effective in POPH.
  • Avoid beta blockers for the treatment of varices in POPH.
• Definitive treatment: liver transplantation

Hepatic hydrothorax ^[42]

• Definition: pleural effusions (typically one-sided; 70% right, 18% left) with transudate characteristics in the absence of any other cardiac, pulmonary, or pleural disease ^[42]
• Pathophysiology: increased permeability of the diaphragm (small defects, increased abdominal pressure)
• Clinical presentation
  • May be asymptomatic
  • Signs and symptoms of pleural effusion: cough, dyspnea, hypoxia
• Diagnosis: Thoracocentesis shows transudate.
• Treatment
  • Medical management: sodium restriction and diuretics
  • Thoracocentesis for symptomatic relief
  • Surgical management for recurrent accumulation
    • Percutaneous drainage
    • Pleurodesis
    • Video-assisted thoracoscopic surgery for the closure of diaphragm defects
    • TIPS
  • Definitive treatment: liver transplantation

Ascites may be absent in up to 20% of cases of hepatic hydrothorax. ^[42]

Other pulmonary complications

• Pneumonia: due to immunosuppression
• Atelectasis: due to an elevated diaphragm in massive ascites
• Lung emphysema: in alpha-1 antitrypsin deficiency

Liver cirrhosis in pregnancy ^[43][44]

• Maternal complications
  • Worsening of liver cirrhosis; pregnancy in individuals with advanced disease is associated with increased risk of:
    • New-onset ascites or worsening of ascites
    • Liver failure
    • Hepatorenal syndrome
    • Variceal bleeding (during pregnancy and/or labor)
  • Increased risk of pregnancy-related complications, including:
    • Gestational diabetes
    • Placental abruption
    • Preeclampsia
    • Postpartum hemorrhage
    • Spontaneous abortion, need of cesarean delivery, preterm delivery
• Fetal complications: associated with increased rates of newborn asphyxia and small size for gestational age