- Clinical science
Cirrhosis is a condition caused by chronic damage to the liver, most commonly due to excessive alcohol consumption or hepatitis C infection. Other causes may include inflammatory or metabolic diseases, such as primary biliary cirrhosis or 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 may present with a range of symptoms, including jaundice, ascites, hepatosplenomegaly, and typical skin manifestations such as spider angioma or palmar erythema. Men may further display signs of feminization (e.g., gynecomastia, hypogonadism). In severe cases, accumulation of toxic metabolites or involvement of further organs can lead to complications such as hepatic encephalopathy or hepatorenal syndrome. Laboratory tests show signs of hepatocyte destruction (e.g., elevated liver enzymes, hyperbilirubinemia) or impaired hepatic synthetic function (e.g., prolonged prothrombin time, low albumin). Abdominal ultrasonography typically shows a shrunken, heterogeneous liver parenchyma with a nodular surface. Biopsy is the method of choice for confirming the diagnosis. However, it is usually only performed if previous testing was inconclusive. Management consists of treatment of the underlying disease (e.g., avoiding toxic substances, antiviral drugs), adequate calorie intake, and medication for treating complications (e.g., spironolactone for ascites). In cases of decompensated cirrhosis, interventional procedures (e.g., paracentesis to drain ascites) may be used to alleviate symptoms or bridge the time until liver transplantation is possible.
- Prevalence: approx. 0.27% in U.S. adults
- Sex: ♂ > ♀ (2:1)
- Responsible for approx. 1–2% of all deaths in the United States; most deaths occurring in the fifth to sixth decade of life
Epidemiological data refers to the US, unless otherwise specified.
- Metabolic disorders
- Cirrhosis of uncertain etiology despite adequate diagnostical efforts
The diagnosis of cryptogenic cirrhosis should be considered only after a thorough, complete evaluation of the patient rules out all other possible causes as the etiology for the cirrhosis.
|Serum albumin g/dL||> 3.5||2.8–3.5||< 2.8|
|Serum bilirubin mg/dL||< 2.0||2.0–3.0||> 3.0|
|INR||< 1.7||1.7–2.3||> 2.3|
|Child-Pugh class A: 5–6 points; Child-Pugh class B: 7–9 points; Child-Pugh class C: 10–15 points|
- Although many factors contribute to the development of cirrhosis, cytokine‑mediated activation of stellate cells has been identified as a central element, as these cells promote fibrosis, which ultimately leads to cirrhosis.
- Hepatic inflammation: → hepatocyte destruction which triggers repair mechanisms → excess formation of connective tissue (fibrosis) → loss of normal liver function (exocrine and metabolic)
- Inflammatory cytokines: → hepatocyte destruction and stellate cell activation → excess collagen production → loss of normal liver function (exocrine and metabolic)
Further pathophysiological mechanisms:
- Intrahepatic shunting between the portal vein and tributaries of the vena cava
- esophageal varices) (→
Impaired liver function
- Decreased synthesis of
- Further possible consequences
- Poor metabolism of medications → accumulation with increased risk of toxicity
- Increased insulin resistance (diabetes mellitus secondary to liver disease)
- Impaired hepatic metabolism of estrogen and androstenedione (which is then converted to estrogen by aromatase in adipose cells) →
- Limited enzymatic activation of vitamin D → secondary hyperparathyroidism
Nonspecific symptoms (patients are often initially asymptomatic)
- Fatigue, malaise, weight loss
- Fetor hepaticus
- Abdominal symptoms
- Skin changes
- Changes in the hepatic metabolization of sex hormones causes an imbalance in the estrogen‑androgen ratio, resulting in a marked increase of systemic estrogen levels. In men, increased estrogen causes feminization. As liver insufficiency worsens, plasma testosterone concentrations decrease.
- Additional clinical signs of rare etiologies of liver cirrhosis
- Signs of hepatocyte destruction
- Signs of impaired hepatic synthesis
- Macrocytic anemia due to vitamin deficiency (B12, folic acid)
- Microcytic anemia due to chronic blood loss
- Thrombocytopenia in hypersplenism
AST-to-platelet-ratio index (APRI)
- Interpretation: APRI > 1 suggests cirrhosis, APRI < 0.5 no cirrhosis.
- Serum protein electrophoresis
Abdominal ultrasound should be performed first. Possible findings include:
- Liver form and structure
Liver size: initially enlarged, atrophies and shrinks with disease progression
- Hypertrophy of the caudate lobe
- Other possible findings
- Loss of intrahepatic portal and liver veins
- Complications of cirrhosis such as .
- CT scan
- Indication: Although biopsy is the gold standard for diagnosis, it is unnecessary in the light of clinical, laboratory, and ultrasound evidence. However, it can aid in identifying the etiology of the cirrhosis if prior testing was inconclusive. Established indications for biopsy are the following:
- Usually ultrasound‑guided transcutaneous approach: easily performed, but may have limited diagnostic value if only a small tissue sample can be taken
- Alternative methods
- Laparoscopic biopsy
- Transjugular biopsy (transvenous biopsy)
Screening procedures and monitoring the disease course
HCC screening: abdominal ultrasound for patients with cirrhosis every 6 months and periodic monitoring of alpha-fetoprotein (AFP)
- Early diagnosis of hepatocellular carcinoma is possible.
- Used to diagnose esophageal varices
- Used to examine patients with portal hypertensive gastropathy
- Factors promoting disease progression:
Before taking a biopsy, check the patient's coagulation status as the risk of bleeding may be increased!
Checklist for diagnosing liver cirrhosis
- What is the Child‑Pugh score?
- What are the causes of the patient's cirrhosis?
- If the cause of the fibrotic changes can be removed, liver tissue that has not yet been irreversably damaged may heal.
- Differential diagnoses
- Wilson's disease: serum and urine copper, serum ceruloplasmin
- Autoimmune hepatitis: hypergammaglobulinemia in the serum protein electrophoresis, AMA, anti‑SMA, anti‑LKM1
- PBC: anti-mitochondrial antibodies (AMA or AMA-M2), ↑ IgM in quantitative immune globulin measurement
- PSC: cholestasis parameters γGT, AP, and ↑ Bilirubin, ↑ pANCA
- Budd‑Chiari syndrome or portal vein thrombosis
- Replacement of normal liver tissue with collagenous regenerative nodules (histological staging is based on the size of the regenerative nodules)
|Size of the regenerative nodules|
|Macronodular||> 3 mm|
|Both||1–3 mm and > 3 mm|| |
- Fibrous septa
- Abnormal cell activation with infiltration of inflammatory cells
- Loss of physiological vessel architecture (central vein disappearance)
- Treatment of the primary condition
- Avoidance of hepatotoxic substances (e.g., alcohol, medication)
- Routine vaccinations; (influenza, pneumococcal disease, hepatitis A/B, tetanus )
- Balanced diet with adequate calorie intake, no protein restriction
- 35–40 kcal pro kg body weight
- Avoidance of a catabolic state through adequate protein intake (1.2–1.5 g protein per kg body weight)
- Supplement branched‑chain fatty acids: In patients with reoccurring decompensation of hepatic encephalopathy.
- Supplemental B vitamins
- Substitute fat‑soluble vitamins if there are signs of malnutrition
Medication (for treatment of complications see respective section)
- Non‑selective beta blockers (e.g., propranolol) to lower portal pressure and prevent variceal bleeding (see treatment of ).
Spironolactone and furosemide to manage ascites and edema in patients with hypoalbuminemia
- In decompensated cirrhosis
Fluid restriction: in the case of ascites and hyponatremia (< 125 mmol/l) → 1.5–2 L daily consumption
- Salt restriction: avoid excessive salt in the diet
- Percutaneous drainage
- Albumin substitution (if more than 5 L fluid has been drained) → 6–8 g human serum albumin per liter ascites
In cases of coagulation factor deficiency (possibly combined with thrombocytopenia): leads to coagulation disturbances and bleeding diathesis
- Treatment with vitamin K substitution
- Vitamin K‑dependent coagulation factors (PPSB) and/or blood plasma should be substituted
- Interventional procedures
- Surgery: A liver transplant is the only curative option in advanced liver disease.
The following complications are covered in separate sections below or in other separate cards:
- Hepatopulmonary syndrome
- Portopulmonary hypertension
- Hepatic hydrothorax
- Tumors (late complication)
- Definition: worsening of liver function in cirrhosis characterized by the presence of jaundice, ascites, variceal hemorrhage, or hepatic encephalopathy
- Hematologic manifestations
Complications caused by portal hypertension
- and subsequent
Metabolic complications or associated organ impairment
- Hepatopulmonary syndrome
We list the most important complications. The selection is not exhaustive.
Definition: Hepatic encephalopathy (HE) is defined as fluctuations in mental status and cognitive function in the presence of severe liver disease. Hepatic dysfunction results in inadequate elimination of metabolic products with subsequent accumulation of neurotoxic metabolites (like ammonia).
- Disturbances of consciousness, ranging from mild confusion to coma
- Multiple neurological and psychiatric disturbances like:
- Elevated blood ammonia levels
- Assessment of mental status
- Number connection test: completed slower than the age-normalized standard or cannot complete
- Psychometry‑based diagnostic method (e.g., , MMSE)
- Critical Flicker Frequency (CFF)
- Rare differential diagnoses: hepatic myelopathy treatable only with a liver transplant.
- Classification of disease severity according to West‑Haven
|Clinical findings||Other findings|
|Stage 0|| || |
Psychometric tests normal
|Stage I|| || |
EEG: triphasic waves
|Stage II|| |
|Stage IV||EEG: delta activity|
- General measures
- Avoidance of trigger substances (e.g., hepatotoxic medication, alcohol)
- Treatment of further complications which might aggravate HE (see “Triggers” above)
Lactulose: synthetic disaccharide laxative
- First-line treatment for HE
- Improves HE by decreasing absorption of ammonia in the bowel: lactulose is 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 → decreased blood ammonia concentration
- Broad spectrum antibiotics: in gastrointestinal bleeding
- General measures
- Definition: deterioration of kidney function in patients with advanced liver disease. The condition is caused by renal vasoconstriction resulting in hypoperfusion of the kidneys.
- Triggers: loss of volume
Diagnostic criteria of hepatorenal syndrome
- Cirrhosis or liver insufficiency with portal hypertension and ascites
- Serum creatinine > 1.5 mg/dL
- Exclusion of other causes of kidney failure
- Creatinine ≥ 1.5 g/dL despite the following measures:
- No proteinuria > 0.5 g/dL, no microhematuria, no acute pathological findings in the kidney ultrasound
- Type I: rapid, within days or weeks (very bad prognosis)
- Type II: long course, progressive over months (better prognosis)
- Oliguria up to anuria with progressive kidney failure
- Clinically associated with decompensated cirrhosis
- Renal water retention leads to edema and hydrops (ascites, pleural, or pericardial effusion)
- General measures: improvement of liver function if possible (e.g., cessation of alcohol use)
- Pharmacotherapy: combination of midodrine, octreotide, and albumin
- Definition: complete or partial closure of the portal vein
- Complication of cirrhosis or chronic liver disease
- Myeloproliferative syndrome
- Thrombophilia (e.g., antiphospholipid syndrome) or general risk factors of phlebothrombosis.
- Chronic mesenteric venous thrombosis
- Local complications of intra-abdominal malignancy (e.g., pancreatic carcinoma) or inflammation (e.g., liver abscess)
- Symptoms: The condition can take many different courses, depending on the extent of thrombosis and the speed of manifestation.
- Color duplex sonography
- CT or MRI of the abdomen with contrast agent
- Treatment with anticoagulants for 3–6 months results in fibrinolysis and recanalization (complete recanalization occurs in about 50% of cases).
- Treatment of complications (such as stopping acute bleeding from esophageal varices)
- Transhepatic thrombolysis with tissue plasminogen activator. Recommended in acute portal vein thrombosis
- Chronic cases may require steady, continuous anticoagulation for as long as local risk factors are present.
- In recurrent bleeding: weigh the danger of bleeding against the consequences of a progressive thrombosis
- Definition: A condition characterized by hypoxemia, intrapulmonary vasodilatation, and portal hypertension in the presence of cirrhosis.
- Pathophysiology: Pulmonary vasodilatation caused by nitric oxide excess in the lung vessels most likely leads tohepatopulmonary syndrome. In addition, portal hypertension leads to the translocation of bacterial endotoxins as well as changes in cytokine production with consequent changes in pulmonary vessel resistance. The pathophysiology is not completely clear, which excludes the possibility for pharmacotherapy.
- Patients may also manifest with platypnea or orthodeoxia
- Definition: portopulmonary hypertension is a form of pulmonary arterial hypertension (PAH), which is associated with portal hypertension. It is a well recognized complication of chronic liver disease.
- Pathogenesis: caused by increased shear stress in the pulmonary circulation in the context of cirrhosis. Vasoactive substances from areas innervated by the splanchnic nerves are considered to play a pathogenic role, as substances bypass hepatic metabolism and reach the pulmonary circulation.
- Clinical findings: same symptoms as
- Diagnostic: echocardiography; right heart catheter for specific diagnostics
- Therapy: supportive measures, no causal therapy
- Definition: mostly one‑sided pleural effusions (85% left, 15% right) with transudate characteristics
- Pathogenesis: caused by increased permeability of the diaphragm on account of micro‑perforations, increased lymphatic leakage and hypoalbuminemia
- Clinical findings: dyspnea (resting)
- Therapy: pleural tap for symptomatic relief
- Further pulmonary complications in cirrhosis
- Survival is poor in patients with decompensated cirrhosis unless they receive liver transplantation.
One‑year survival rate based on Child‑Pugh score:
- Child‑Pugh class A: almost normal
- Child‑Pugh class B: 80%
- Child‑Pugh class C: 45%
Mortality (risk assessed according to clinical criteria)