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Gastroenterology - Liver Cirrhosis - Fast Facts | NEJM Resident 360

Cirrhosis is defined as irreversible fibrosis of the liver and is the final stage of chronic liver disease following years of progression. Clinically, cirrhosis begins as compensated disease, followed by a decompensated phase characterized by ascites, jaundice, variceal bleeding, and encephalopathy. Progression of decompensated cirrhosis leads eventually to liver transplantation or death. In this section, we review liver cirrhosis and associated complications.

Causes

The most common causes of cirrhosis are alcoholic liver disease, viral hepatitis, and nonalcoholic fatty liver disease. However, cirrhosis can occur due to a range of liver diseases, as outlined in the following table:

Causes of Liver Cirrhosis
Fatty liver diseases

• Alcoholic liver disease

• Nonalcoholic steatohepatitis (NASH) 

| Viral

• Hepatitis B

• Hepatitis C

• Hepatitis D

| | Hereditary

• Hemochromatosis

• Wilson disease

• Alpha₁-antitrypsin deficiency

| Autoimmune

• Primary biliary cirrhosis

• Primary sclerosing cholangitis

• Autoimmune hepatitis

| | Chronic biliary disease

• Mechanical bile-duct obstruction

• Recurrent bacterial cholangitis

| Cardiovascular

• Budd–Chiari syndrome

• Right-heart failure

|

Diagnosis

The gold standard for diagnosing cirrhosis is liver biopsy. However, the following noninvasive tests can assist in diagnosis and staging:

• Liver biopsy confirms the diagnosis of liver disease and provides information on fibrosis stage, etiology, type of inflammation, and degree of steatosis.

• Vibration-controlled transient liver elastography is used increasingly as a noninvasive alternative to liver biopsy.

• • Readings are unreliable in obese (BMI >30 kg/m²) or older patients or in those with ascites.

  • Median stiffness <7.0 kilopascal (kPa) is considered normal (found in 90%–95% of healthy people without liver disease).

  • Median stiffness >17.0 kPa suggests clinically significant portal hypertension.

• Abdominal ultrasound is useful for assessing liver texture, portal hypertension, portal vein thrombosis, hepatocellular carcinomas, and biliary tract obstruction.

• Magnetic resonance imaging (MRI) can be used to assess fatty liver disease and to quantify fat and iron content, evaluate tumors and space-occupying lesions, and assess the biliary and pancreatic ducts.

Other investigations that can assess liver synthetic function and complications of cirrhosis include:

• Complete blood count: Thrombocytopenia and anemia are common in cirrhosis.

• International normalized ratio (INR), ammonia, bilirubin, and albumin are markers of synthetic function.

• Biochemistry: Hyponatremia is common due to antidiuretic hormone release and subsequent water retention in portal hypertension.

• Viral serologies and viral load for hepatitis B and C

Classification

The Child–Turcotte–Pugh classificationis used to stratify patients with cirrhosis and to assess disease prognosis. It is based on clinical features of end-stage liver disease (e.g., ascites and hepatic synthetic function).

Child–Turcotte–Pugh Classification

Points	1	2	3
Ascites	Absent	Suppressed with medication	Refractory
Encephalopathy	None	Minimal, grades 1–2
(or suppressed with medication)	Advanced, grades 3–4 (or refractory)
Bilirubin (μmol/L)	<34	34–50	>50
Albumin (g/L)	>35	28–35	<28
INR	<1.7	1.7–2.2	>2.2

Abbreviation: INR, international normalized ratio

The higher the Child–Pugh score, the poorer the prognosis: Child–Pugh A = 5–6 points, Child–Pugh B = 7–9 points, Child–Pugh C = ≥10 points

Treatment

Treatment of underlying disease: When possible, treat the underlying disease. The following table summarizes therapies used to treat common causes of cirrhosis:

Common Causes of Cirrhosis and Associated Treatment

Cause	Treatment
Hepatitis C	New direct-acting antiviral therapy
Hepatitis B	Interferon, nucleoside or nucleotide analogues (e.g., tenofovir or entecavir)
Alcohol	Abstinence
NASH	Lifestyle changes: dietary restriction (500–1000 kcal deficit), physical activity,
weight loss (target of 7%–10%)

Diabetic control

Bariatric surgery | | Autoimmune hepatitis | Prednisone, budesonide, azathioprine | | Hemochromatosis | Phlebotomy | | Wilson disease | D-penicillamine | | Primary biliary cholangitis | Ursodeoxycholic acid | | Budd–Chiari syndrome | Transjugular intrahepatic portosystemic shunt (TIPS)

Liver transplant |

**
Management of cirrhosis:** Treatment of cirrhosis focuses on prevention of further disease progression and preventing complications. A suggested clinical approach is outlined in the following algorithm:

Algorithm for the Treatment of Patients with Cirrhosis

(Source: Treatment of Patients with Cirrhosis. N Engl J Med 2016.)

Complications of Cirrhosis

If the natural history of cirrhosis cannot be interrupted, severe and life-threatening complications can develop and require urgent hospital admission. The morbidity and mortality associated with cirrhosis are primarily related to the following complications:

Portal hypertension and variceal bleeding:

• Increasing fibrosis leads to increased pressures (portal hypertension) throughout the portal circulation; measurement of hepatic venous pressure gradient (HVPG) is an indicator of the severity of portal hypertension.

• Portal hypertension leads to the formation of portosystemic venous collaterals in the splanchnic circulation, giving rise to esophageal and gastric varices, hemorrhoids, and caput medusae on the abdominal wall.

• Esophageal varices can be classified by diameter (generally, small varices are ≤5 mm and medium/large varices are >5 mm).

• Acute variceal bleeding is a medical emergency requiring urgent inpatient management, including endoscopic control of bleeding, vasoconstrictors, antibiotic, proton pump inhibitor, and blood transfusion to control bleeding and prevent early rebleeding and death.

• In patients suspected of having varices who have not yet had an acute gastrointestinal bleed, endoscopic surveillance is recommended to eliminate varices by banding.

• Nonselective beta-blockers (e.g., propranolol, nadolol, and carvedilol) can be used to reduce portal pressure and risk of acute variceal bleeding.

• All patients with medium or large varices should receive primary prophylaxis for variceal hemorrhage with a nonselective beta blocker or endoscopic variceal ligation.

• A transjugular intrahepatic portosystemic shunt (TIPS) can also be used to reduce portal vein pressures and as an alternative to surgery for acute decompression of portal hypertension.

Ascites:

• Ascites is the pathologic accumulation of fluid in the peritoneal cavity as a result of portal hypertension.

• Complications of ascites are infection, refractory or recurrent ascites, and association with hepatorenal syndrome.

• Diuretic treatment (with spironolactone and furosemide) of uncomplicated ascites follows a stepwise pattern, aiming for maximum weight loss of 0.5–1 kg/day.

Spontaneous bacterial peritonitis:

• Patients with ascites and cirrhosis who present with abdominal pain and fever and feel unwell should undergo diagnostic paracentesis to evaluate for spontaneous bacterial peritonitis (SBP).

• Ascitic leukocytes >500 cells/μL or ascitic fluid polymorphonuclear (PMN) leukocyte counts >250 cells/μL are diagnostic of SBP.

• Treatment includes empiric broad-spectrum antibiotics (e.g., ceftriaxone or cefotaxime) until results of cultures and antibiotic sensitivities are available.

• Administration of albumin has been shown to reduce mortality in patients with SBP.

• Long-term SBP prophylaxis is indicated in patients with a previous episode of SBP who meet certain other criteria (e.g., previous history of SBP or low ascitic protein). Recommended agents include norfloxacin, trimethoprim–sulfamethoxazole, or ciprofloxacin.

Hepatopulmonary syndrome:

• Hepatopulmonary syndrome is defined as a triad of cirrhosis, pulmonary gas-exchange abnormalities, and evidence of intrapulmonary vascular dilatation.

• Clinical features include dyspnea, platypnea (dyspnea exacerbated by sitting up and improved with lying down), and orthodeoxia (arterial deoxygenation with PaO₂ decrease ≥5% or 4 mm Hg from supine to upright position), resulting from preferential perfusion of the lung bases, and functional shunting when the patient is upright.

• Oxygen supplementation may be required in some patients.

• Definitive treatment is liver transplantation.

Hepatic encephalopathy:

• Hepatic encephalopathy is a brain dysfunction caused by liver insufficiency.

• The most common precipitating factors include infections, gastrointestinal bleeding, diuretic overdose, electrolyte disorders, and excess dietary protein.

• Ammonia is the main surrogate marker of hepatic encephalopathy, but blood ammonia concentration is poorly correlated with the degree of psychomotor dysfunction.

• Treatment of hepatic encephalopathy involves:

• • elimination of precipitating factors (e.g., GI bleeding, renal failure, and infection)

  • maintenance of a normal protein diet

  • reduction in colonic ammonia production with oral lactulose (20–30 mL daily) as needed with the aim of two to three soft stools per day

  • oral rifaximin is recommended for secondary prophylaxis of overt hepatic encephalopathy not responsive to lactulose

Hepatorenal syndrome

• Hepatorenal syndrome (HRS) is a state of potentially reversible renal dysfunction, with two subtypes:

• • Type 1: acute HRS associated with rapid deterioration of renal function (doubling of initial serum creatinine to >2.5mg/dL or by 50% reduction in creatinine clearance to <20mL/min in <2 weeks)

  • Type 2: moderate, steady renal failure with serum creatinine >1.5 mg/dL for weeks to months.

• First-line treatment consists of vasoconstrictors and albumin. 

• Definition of acute kidney injury in patients with cirrhosis: 

  • increase in sCr ≥0.3 mg/dL within 48 hours, or

  • a percentage increase in sCr ≥50% from baseline (known or presumed to have occurred within the prior 7 days)

Hepatocellular carcinoma:

• Liver cirrhosis is considered precancerous, although time of progression to hepatocellular carcinoma (HCC) varies depending on the underlying disease.

• In patients with cirrhosis secondary to chronic hepatitis C virus infection, the annual incidence of HCC is 1%–8%; in patients with cirrhosis secondary to chronic hepatitis B virus (HBV) infection, the annual incidence of HCC is 1%–15%.

• Worldwide, HBV infection is the main cause of HCC and can occur in the absence of cirrhosis.

• Hepatitis B vaccination of infants and children has resulted in a marked decrease in incidence.

• If a liver nodule is detected on screening ultrasonography, the following diagnostic algorithm can be used:

Diagnostic Algorithm for a Liver Nodule in a Patient with Cirrhosis

(Source: Hepatocellular Carcinoma. N Engl J Med 2019.)

• A range of treatments are available for HCC depending on stage of disease, including tumor ablation, resection, transarterial therapies, and systemic therapies.

• Liver transplantation may be an option for patients with small or localized HCC.

Read this review article for a detailed overview of hepatocellular carcinoma diagnosis and treatment.

Liver Transplantation

Patients with cirrhosis should be considered for liver transplantation if they have had an index complication such as ascites, hepatic encephalopathy or variceal hemorrhage, or hepatocellular dysfunction resulting in a Model for End-Stage Liver Disease (MELD) score ≥15. MELD is based on creatinine, bilirubin, international normalized ratio (INR), and sodium levels. Transplantation is considered the last option for management. As with all organ transplantation, detailed patient workup is required prior to consideration.

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