Cirrhosis; Causes, Symptoms, Diagnosis, Treatment

Cirrhosis is defined as the histological development of regenerative nodules surrounded by fibrous bands in response to chronic liver injury, which leads to portal hypertension and end-stage liver disease. Recent advances in the understanding of the natural history and pathophysiology of cirrhosis, and in treatment of its complications, have resulted in improved management, quality of life, and life expectancy of patients. Liver transplantation remains the only curative option for a selected group of patients, but pharmacological treatments that can halt progression to decompensated cirrhosis or even reverse cirrhosis are currently being developed. This Seminar focuses on the diagnosis, complications, and management of cirrhosis, and new clinical and scientific developments.

Types of Cirrhosis

Cirrhosis is classified based on morphology or etiology.

Morphology

Morphologically, cirrhosis is (1) micronodular, (2) macronodular, or (3) mixed. This classification is not as clinically useful as etiologic classification.

  • Micronodular cirrhosis (uniform nodules less than 3 mm in diameter) – Cirrhosis due to alcohol, hemochromatosis, hepatic venous outflow obstruction, chronic biliary obstruction, jejunoileal bypass, and Indian childhood cirrhosis.
  • Macronodular cirrhosis (irregular nodules with a variation greater than 3 mm in diameter) – Cirrhosis due to hepatitis B and C, alpha-1 antitrypsin deficiency, and primary biliary cholangitis.
  • Mixed cirrhosis (when features of both micronodular and macronodular cirrhosis are present) – Usually micronodular cirrhosis progresses into macronodular cirrhosis over time.

Etiology

Etiologic classification is based on the cause of cirrhosis which is sub-classified as follows:

  • Viral – hepatitis B, C, and D
  • Toxins – alcohol, drugs
  • Autoimmune – autoimmune hepatitis
  • Cholestatic – primary biliary cholangitis, primary sclerosing cholangitis
  • Vascular – Budd-Chiari syndrome, sinusoidal obstruction syndrome, cardiac cirrhosis
  • Metabolic – hemochromatosis, NASH, Wilson disease, alpha-1 antitrypsin deficiency, cryptogenic cirrhosis.

Causes of Cirrhosis

Liver cirrhosis has many possible causes; sometimes more than one cause is present in the same person. Globally, 57% of cirrhosis is attributable to either hepatitis B (30%) or hepatitis C (27%).[rx] Alcohol consumption is another major cause, accounting for about 20% of the cases.[rx]

  • Alcoholic liver disease (ALD) – Alcoholic cirrhosis develops for 10–20% of individuals who drink heavily for a decade or more.[rx] Alcohol seems to injure the liver by blocking the normal metabolism of protein, fats, and carbohydrates. This injury happens through the formation of acetaldehyde from alcohol which itself is reactive, but which also leads to the accumulation of other reactive products in the liver.[rx] Patients may also have concurrent alcoholic hepatitis with fever, hepatomegaly, jaundice, and anorexia. AST and ALT blood levels are both elevated, but at less than 300 IU/liter, with an AST:ALT ratio > 2.0, a value rarely seen in other liver diseases.[rx] In the United States, 40% of cirrhosis-related deaths are due to alcohol.[rx]
  • Non-alcoholic steatohepatitis (NASH) – In NASH, fat builds up in the liver and eventually causes scar tissue. This type of hepatitis appears to be associated with obesity (40% of NASH patients) diabetes, protein malnutrition, coronary artery disease, and treatment with steroid medications. This disorder is similar in it signs to alcoholic liver disease, but the patient does not have an alcohol history. A biopsy is needed for diagnosis.[rx]
  • Chronic hepatitis C – Infection with the hepatitis C virus causes inflammation of the liver and a variable grade of damage to the organ. Over several decades, this inflammation and damage can lead to cirrhosis. Among patients with chronic hepatitis C, 20–30% will develop cirrhosis.[rx][rx] Cirrhosis caused by hepatitis C and alcoholic liver disease are the most common reasons for liver transplant.[rx]
  • Chronic hepatitis B – The hepatitis B virus causes liver inflammation and injury that over several decades can lead to cirrhosis. Hepatitis D is dependent on the presence of hepatitis B and accelerates cirrhosis in co-infection.[rx]
  • Primary biliary cholangitis (also known as primary biliary cirrhosis) – The bile ducts become damaged by an autoimmune process, leading to secondary liver damage. Patients may be asymptomatic or have fatigue, pruritus, and non-jaundice skin hyperpigmentation with hepatomegaly. There is prominent alkaline phosphatase elevation as well as elevations in cholesterol and bilirubin and usually positive anti-mitochondrial antibodies.
  • Primary sclerosing cholangitis – PSC is a progressive cholestatic disorder presenting with pruritus, steatorrhea, fat-soluble vitamin deficiencies, and metabolic bone disease. There is a strong association with inflammatory bowel disease (IBD), especially ulcerative colitis.[rx]
  • Autoimmune hepatitis – This disease is caused by an attack of the liver by lymphocytes, causing inflammation and eventually scarring and cirrhosis. Findings include elevations in serum globulins, especially gamma globulins.[rx]
  • Hereditary hemochromatosis – Usually presents with a family history of cirrhosis, skin hyperpigmentation, diabetes mellitus, pseudogout, or cardiomyopathy, all due to signs of iron overload.[rx][rx]
  • Wilson’s disease – An autosomal recessive disorder characterized by low serum ceruloplasmin and increased hepatic copper content on liver biopsy and elevated 24-hour urine copper. May also have Kayser-Fleischer rings in the cornea and altered mental status.
  • Indian childhood cirrhosis – is a form of neonatal cholestasis characterized by deposition of copper in the liver.[rx]
  • Alpha 1-antitrypsin deficiency (A1AD) – Autosomal recessive disorder of decreased levels of the enzyme alpha 1—antitrypsin.[rx]
  • Hepatitis B – Hepatitis B can cause liver inflammation and damage that can lead to cirrhosis.
  • Hepatitis D – This type of hepatitis can also cause cirrhosis. It’s often seen in people who already have hepatitis B.
  • Inflammation caused by autoimmune disease – Autoimmune hepatitis may have a genetic cause. According to the American Liver Foundation[rx], about 70 percent of people with autoimmune hepatitis are women.
  • Damage to the bile ducts which function to drain bile – One example of such a condition is primary biliary cirrhosis.
  • Disorders that affect the body’s ability to handle iron and copper – Two examples are hemochromatosis and Wilson’s disease.
  • Medications -Medications includingprescription and over-the-counter drugs like acetaminophen, some antibiotics, and some antidepressants, can lead to cirrhosis.
  • Cardiac cirrhosis[rx]. Due to chronic right sided heart failure, which leads to liver congestion.[rx]
  • Galactosemia
  • Glycogen storage disease type IV
  • Cystic fibrosis[rx]
  • Hepatotoxic drugs or toxins
  • Chronic alcohol abuse
  • Chronic viral hepatitis (hepatitis B, C and D)
  • Fat accumulating in the liver (nonalcoholic fatty liver disease)
  • Iron buildup in the body (hemochromatosis)
  • Copper accumulated in the liver (Wilson’s disease)
  • Poorly formed bile ducts (biliary atresia)
  • Alpha-1 antitrypsin deficiency
  • Inherited disorders of sugar metabolism (galactosemia or glycogen storage disease)
  • Genetic digestive disorder (Alagille syndrome)
  • Liver disease caused by your body’s immune system (autoimmune hepatitis)
  • Destruction of the bile ducts (primary biliary cirrhosis)
  • Hardening and scarring of the bile ducts (primary sclerosing cholangitis
  • Infection, such as syphilis or brucellosis
  • Medications, including methotrexate or isoniazid.

Symptoms of Cirrhosis

Cirrhosis often has no signs or symptoms until liver damage is extensive. When signs and symptoms do occur, they may include:

  • Fatigue
  • Easily bleeding or bruising
  • Loss of appetite
  • Nausea
  • Swelling in your legs, feet or ankles (edema)
  • Weight loss
  • Itchy skin
  • Yellow discoloration in the skin and eyes (jaundice)
  • Fluid accumulation in your abdomen (ascites)
  • Spiderlike blood vessels on your skin
  • Redness in the palms of the hands
  • For women, absent or loss of periods not related to menopause
  • For men, loss of sex drive, breast enlargement (gynecomastia) or testicular atrophy
  • Confusion, drowsiness and slurred speech (hepatic encephalopathy)
  • Confusion and difficulty thinking clearly
  • Abdominal swelling (ascites)
  • Swelling of the legs (edema)
  • Impotence
  • Gynecomastia (when males start to develop breast tissue)
  • Feel very tired and weak
  • Feel nauseous
  • Lose your sex drive
  • Yellowing of the skin and whites of the eyes (jaundice)
  • Vomiting blood
  • Itchy skin
  • Dark, tarry-looking poo
  • A tendency to bleed or bruise more easily
  • Swollen legs (oedema) or tummy (ascites) from a build-up of fluid

Later symptoms, as the liver is struggling to function

  • Intensely itchy skin
  • Yellowing of the whites of the eyes and the skin (jaundice)
  • White nails
  • Ends of fingers become wider/thicker (clubbed fingers)
  • Hair loss
  • Swelling of the legs, ankles, feet (oedema)
  • Swelling of the abdomen (ascites)
  • Dark urine
  • Pale-coloured stools or very dark/black tarry stools
  • Frequent nosebleeds and bleeding gums
  • Easy bruising and diffi culty in stopping small bleeds
  • Vomiting blood
  • Frequent muscle cramps
  • Right shoulder pain
  • Enlarged breasts and shrunken testes
  • Irregular or lack of menstrual periods
  • Impotence and loss of sexual desire
  • dizziness and extreme fatigue (anaemia)
  • Shortness of breath
  • Very rapid heartbeat (tachycardia)
  • Fevers with high temperature and shivers
  • Forgetfulness, memory loss, confusion, and drowsiness
  • The subtle change in personality
  • Trembling hands
  • Writing becomes difficult, spidery and small
  • Staggering gait when walking; tendency to fall
  • Increased sensitivity to drugs, both medical and recreational
  • Increased sensitivity to alcohol

Red flag symptoms

If you have any of the following symptoms you must see a doctor straight away, especially if you have recently been diagnosed with cirrhosis:

  • Fever with high temperatures and shivers, often caused by an infection
  • Shortness of breath
  • Vomiting blood
  • Very dark or black tarry stools (faeces)
  • Periods of mental confusion or drowsiness.

Although these symptoms may seem very different, because your liver is responsible for so many different functions, if it stops working properly, a range of problems can result.

Clinical Features of Cirrhosis

GENERAL FINDINGS a DESCRIPTION ETIOLOGY REFs
Jaundice Yellow discoloration of skin, cornea and mucous membranes Compromised hepatocyte excretory function, occurs when serum bilirubin >2mg/dl –
Spider angiomata Central arteriole with tiny radiating vessels, mainly on trunk and face Elevated estradiol, decreased estradiol degradation in liver ,
Nodular liver Irregular, hard surface on palpation Fibrosis, irregular regeneration
Splenomegaly Enlarged on palpation or in ultrasound Portal hypertension, splenic congestion
Ascites Proteinaceous fluid in abdominal cavity, clinically detected when ≥1.5 L Portal hypertension –
Caput medusae Prominent veins radiating from umbilicus Portal hypertension, reopening of the umbilical vein that shunts blood from the portal vein
Cruveilhier Baumgarten syndrome Epigastric vascular murmur Shunts from portal vein to umbilical vein branches, can be present without Caput medusae
Palmar erythema Erythema sparing the central portion of the palm Elevated estradiol, decreased estradiol degradation in liver –
White nails Horizontal white bands and/or proximal white nail plate Hypoalbuminemia
Hypertrophic osteoarthropathy/Finger clubbing Painful proliferative osteoarthropathy of long bones Hypoxemia due to right-to-left shunting, porto-pulmonary hypertension
Dupuytren’s contracture Fibrosis and contraction of the palmar fascia Enhanced oxidative stress, elevated hypoxanthine (alcohol exposure or diabetes)
Gynecomastia, loss of male hair pattern Benign proliferation of glandular male breast tissue Enhanced conversion of androstenedione to estrone and estradiol, decreased estradiol degradation in liver
Hypogonadism Mainly in alcoholic cirrhosis and hemochromatosis Direct toxic effect of alcohol or iron –
Flapping tremor (asterixis) Asynchronous flapping motions of dorsiflexed hands Hepatic encephalopathy, disinhibition of motor neurons –
Foetor hepaticus Sweet, pungent smell Volatile dimethylsulfide, especially in portosystemic shunting and liver failure
Anorexia, fatigue, weight loss, muscle wasting Occurs in >50% of cirrhotics Catabolic metabolism by diseased liver, secondary to anorexia –
Type 2 diabetes Occurs in 15-30% of cirrhotics Disturbed glucose utilization and/or decreased insulin removal by the liver –

Multiple Organs Affected

  • Gastrointestinal – Portal hypertension can cause ascites, hepatosplenomegaly, and prominence of the periumbilical abdominal veins resulting in caput medusa. Esophageal varices are another complication of cirrhosis secondary to increased blood flow in the collateral circulation, with a mortality rate of at least 20% at six weeks after a bleeding episode. Patients with alcoholic cirrhosis are at increased risk of small bowel bacterial overgrowth and chronic pancreatitis, and patients with chronic liver disease have a higher rate of gallstones formation.
  • Hematologic – Anemia can occur due to folate deficiency, hemolytic anemia (spur cell anemia in severe alcoholic liver disease), and hypersplenism. There can be pancytopenia due to hypersplenism in portal hypertension, impaired coagulation, disseminated intravascular coagulation, and hemosiderosis in patients with cirrhosis due to different causes.
  • Renal – Patients with cirrhosis are prone to develop hepatorenal syndrome secondary to systemic hypotension and renal vasoconstriction, causing the underfilling phenomenon. Splanchnic vasodilation in cirrhosis leads to decreased effective blood flow to the kidneys, which activates the RAAS system, leading to retention of sodium and water and renal vascular constriction. However, this effect is not enough to overcome the systemic vasodilation caused by cirrhosis, leading to renal hypoperfusion and worsened by renal vasoconstriction with the end point of renal failure.
  • Pulmonary – Manifestations of cirrhosis include hepatopulmonary syndrome, portopulmonary hypertension, hepatic hydrothorax, decreased oxygen saturation, ventilation-perfusion mismatch, reduced pulmonary diffusion capacity, and hyperventilation.
  • Skin – Spider nevi (central arterioles surrounded by multiple smaller vessels that look like a spider, hence the name) are seen in patients with cirrhosis secondary to hyperestrogenemia. Liver dysfunction leads to a sex hormone imbalance, causing increased estrogen to free testosterone ratio and the formation of spider nevi. Palmer erythema is another skin finding that is seen in cirrhosis and is also secondary to hyperestrogenemia. Jaundice is a yellowish discoloration of the skin and mucous membranes that is seen when the serum bilirubin is greater than 3 mg/dL and in decompensated cirrhosis.
  • Endocrine – Patients with alcoholic liver cirrhosis can develop hypogonadism and gynecomastia. The pathophysiology is multifactorial, mainly due to hypersensitivity of estrogen and androgen receptors seen in cirrhotic patients. Hypothalamic-pituitary dysfunction has also been implicated in the development of these conditions. Hypogonadism can lead to decreased libido and impotence in males with a loss of secondary sexual characteristics and feminization. Women can develop amenorrhea and irregular menstrual bleeding as well as infertility.
  • Nail changes – Clubbing, hypertrophic osteoarthropathy, and the Dupuytren contracture are seen. Other nail changes include azure lunules (Wilson disease), Terry nails and Muercke nails.
  • Others – Fetor hepaticus (sweet musty breath smell due to high levels of dimethyl sulfide and ketones in the blood) and asterixis (flapping tremor when the arms are extended and the hands are dorsiflexed) are both features of hepatic encephalopathy that can be seen in cirrhosis. Cirrhosis can lead to a hyperdynamic circulation, reduction in lean muscle mass, muscle cramps, and umbilical herniation.

Diagnosis of Cirrhosis

Physical examination

  • Cirrhosis may reveal stigmata of chronic liver disease (spider telangiectasias, palmar erythema, Dupuytren’s contractures, gynecomastia, testicular atrophy),
  • Signs of portal hypertension (ascites, splenomegaly, caput medusae, Cruveilhier-Baumgarten murmur- epigastric venous hum), signs of hepatic encephalopathy (confusion, asterixis and fetor hepaticus),
  • Other features such as jaundice, bilateral parotid enlargement, and scant chest/axillary hair.

The typical findings in cirrhosis include

  • cutaneous signs of liver disease,
  • a firm liver on palpation, and
  • certain risk constellations such as:
  • metabolic syndrome
  • heavy alcohol consumption
  • exposure to hepatotoxic substances
  • use of hepatotoxic medications [, .

The early signs of cirrhosis in B-ultrasonography include inhomogeneity of the hepatic tissue, irregularity of the hepatic surface, or enlargement of the caudate lobe. Portal hypertension leads to splenomegaly.

Lab Findings

The following findings are typical in cirrhosis:

  • Thrombocytopenia – typically multifactorial. Due to alcoholic marrow suppression, sepsis, lack of folate, platelet sequestering in the spleen as well as decreased thrombopoietin.[rx] However, this rarely results in a platelet count < 50 000/mL.[rx]
  • Aminotransferases – AST and ALT are moderately elevated, with AST > ALT. However, normal aminotransferase levels do not preclude cirrhosis.[rx]
  • Alkaline phosphatase – slightly elevated but less than 2–3 times the upper limit of normal.
  • Gamma-glutamyl transferase – correlates with AP levels. Typically much higher in chronic liver disease from alcohol.[rx]
  • Bilirubin – Levels normally when compensated but may elevate as cirrhosis progresses.
  • Albumin – levels fall as the synthetic function of the liver declines with worsening cirrhosis since albumin is exclusively synthesized in the liver
  • Prothrombin time – increases, since the liver synthesizes clotting factors.
  • Globulins – increased due to the shunting of bacterial antigens away from the liver to lymphoid tissue.
  • Serum sodium – hyponatremia due to inability to excrete free water resulting from high levels of ADH and aldosterone[rx].
  • Leukopenia and neutropenia – due to splenomegaly with splenic margination.
  • Coagulation defects – the liver produces most of the coagulation factors and thus coagulopathy correlates with worsening liver disease.
  • Glucagon – increased in cirrhosis[rx]
  • Vasoactive intestinal peptide – increased as blood is shunted in the intestinal system because of portal hypertension
  • Vasodilators – increased (such as nitric oxide and carbon monoxide) reducing afterload with a compensatory increase in cardiac output, mixed venous oxygen saturation[rx]
  • Renin – increased (as well as sodium retention in kidneys) secondary to fall in systemic vascular resistance[rx]
  • FibroTest – is a biomarker for fibrosis that can be done instead of a biopsy.[rx]

Other laboratory studies performed in newly diagnosed cirrhosis may include

  • Serology for hepatitis viruses, autoantibodies (ANA, anti-smooth muscle, anti-mitochondria, anti-LKM)
  • Ferritin and transferrin saturation: markers of iron overload as in hemochromatosis, copper and ceruloplasmin: markers of copper overload as in Wilson’s disease
  • Immunoglobulin levels (IgG, IgM, IgA) – these immunoglobins are non-specific, but may help in distinguishing various causes
  • Cholesterol and glucose
  • Alpha 1-antitrypsin

Lab Findings

  • Aminotransferases are usually mildly to moderately elevated with aspartate aminotransferase (AST) greater than alanine aminotransferase (ALT); however, normal levels do not exclude cirrhosis.
  • In most forms of chronic hepatitis (except alcoholic hepatitis), the AST/ALT ratio is less than one. As chronic hepatitis progresses to cirrhosis, there is a reversal of this AST/ALT ratio. Alkaline phosphatase (ALP), 5′- nucleotidase, and gamma-glutamyl transferase (GGT) are elevated in cholestatic disorders.
  • Prothrombin time (PT) is elevated due to coagulation factor defects as well as bilirubin, while albumin is low as it is synthesized by the liver and the liver’s functional capacity goes down.

Specific Labs to Investigate Newly Diagnosed Cirrhosis

  • Serology and PCR techniques for viral hepatitis and autoimmune antibodies (anti-nuclear antibodies [ANA], anti-smooth muscle antibodies (ASMA), Anti-liver-kidney microsomal antibodies type 1 (ALKM-1) and serum IgG immunoglobulins) for autoimmune hepatitis and anti-mitochondrial antibody for primary biliary cholangitis may be ordered.
  • Ferritin and transferrin saturation for hemochromatosis, ceruloplasmin and urinary copper for Wilson disease, Alpha 1-antitrypsin level and protease inhibitor phenotype for Alpha 1-antitrypsin deficiency, and serum alpha-fetoprotein for hepatocellular carcinoma (HCC) are other useful tests.

Imaging and Liver Biopsy

  • A number of imaging modalities are used alongside with labs to help in the diagnosis of cirrhosis. These include ultrasound, CT, MRI, and transient elastography (fibroscan).
  • Ultrasonography –  is a cheap, noninvasive, and available modality for the evaluation of cirrhosis. It can detect nodularity and increased echogenicity of the liver, which are seen in cirrhosis; however, it is nonspecific as these findings can be seen in fatty liver as well. It can also determine the ratio of the caudate lobe width to right lobe width which usually increases in cirrhosis. Moreover, it is a useful screening tool for HCC in cirrhotic patients. Duplex Doppler ultrasonography helps to assess the patency of hepatic, portal, and mesenteric veins.
  • CT and MRI – with contrast can be used to detect HCC and vascular lesions, with MRI being superior to CT. MRI also can be used to detect the level of iron and fat deposition in the liver for hemochromatosis and steatosis, and biliary obstruction if an MRC (magnetic resonance cholangiography) is obtained. MRI, however, is expensive and not readily available.
  • Transient elastography (fibroscan) – is a noninvasive method that uses high velocity ultrasound waves to measure liver stiffness which correlates with fibrosis. In cirrhosis, a colloid liver spleen scan using technetium-99m sulfur colloid may show increased uptake of colloid in the bone marrow and spleen when compared to the liver. Presence of varices in the esophagus or stomach on esophagogastroduodenoscopy (EGD) suggests portal hypertension.
  • Liver biopsy  – in which a tiny piece of the liver is taken to be looked at under a microscope. A fine hollow needle is passed through the skin into the liver and a small sample is withdrawn. The test is usually done under local anesthetic and may mean an overnight stay in the hospital, although most people are allowed home later the same day if they live close by.
  • Endoscopy – in which, following sedation, a thin flexible tube with a light and a tiny camera on the end (endoscope) is passed down your esophagus and into your stomach. This is to check for variances in the esophagus or stomach which may rupture and suddenly bleed.

Laboratory Findings in Cirrhosis

LABORATORY TEST a DESCRIPTION ETIOLOGY
AST and ALT Often normal or moderately elevated Leakage from damaged hepatocytes; AST to ALT ratio often above 1, especially in alcoholic cirrhosis (relative vitamin B6 deficiency)
ALP Elevated <3-fold, except for PBC and PSC Cholestasis
GGT More specific for the liver than ALP, high in active alcoholics Cholestasis
Bilirubin Elevated later than GGT and ALP, an important predictor of mortality Cholestasis decreased hepatocyte and renal excretory function (exacerbated by systemic inflammation)
Albumin Decreased in advanced cirrhosis Decreased hepatic production, sequestration into ascites and interstitium (exacerbated in systemic inflammation), DD: malnutrition, protein-losing enteropathy
Prothrombin time Decreased in advanced cirrhosis Decreased hepatic production of factor V/VII (While thrombin production is maintained), DD: vitamin K deficiency (e.g., due to mechanical biliary obstruction)
Immune globulins Increased (mainly IgG) Shunting of portal venous blood carrying (intestinal) antigens to lymph tissues with resultant stimulation of plasma cells [
Sodium imbalance Hyponatremia Unability to excrete free water via the kidneys due to increased activity of antidiuretic hormone (vasopressin 2 receptor effect) [
Anemia Macro-, normo- or microcytic anemia Folate deficiency, hypersplenism, direct toxicity (alcohol), gastrointestinal blood loss (e.g., via esophageal varices)
Thrombocytes and leukocytes Thrombocytopenia (Leukopenia) Hypersplenism, dysfibronogenemia, reduced hepatic thrombopoietin production [

Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; DD, differential diagnosis; GGT, gamma-glutamyl transpeptidase; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis

Diagnostic tests in chronic liver disease

ETIOLOGY SPECIFIC PHYSICAL ASSOCIATIONS DIAGNOSTIC (LABORATORY) PARAMETERS VALUE OF LIVER BIOPSY
HBV Arthritis HBsAg, (HBeAg), anti-HBc, HBV-DNA +
HCV Cryoglobulinemia, anti-HCV, HBV-RNA +
HDV (HBsAg), anti-HDV, HDV-RNA ++ (HDAg)
Alcoholic AST/ALT ≥2, CDT↑, γGT↑ ++ (Mallory bodies, steatosis, granulocytes >hepatocyte ballooning)
NASH Overweight/obesity, metabolic syndrome, type 2 diabetes Uric acid, fasting glucose/insulin/triglycerides, ++ (Mallory bodies, steatosis, hepatocyte ballooning>granulocytes)
Autoimmune Autoantibodies (ANA, anti-LKM, anti-SLA), γ-globulins↑↑ +++ (bridging necrosis)
PBC Sicca-syndrome, xanthelasma AMA, ALP/γGT↑, cholesterol↑ ++ (cholangitis, paucity of bile ducts, granuloma, ductopenia)
PSC Ulcerative colitis (90%) Anti-pANCA (70%), ALP/γGT↑
imaging: beaded intra- (and extra-) hepatic bile ducts		 +++ (concentric peri-bile ductular fibrosis, ductopenia)
Hemochromatosis Arthritis, myocarditis, diabetes Fasting transferrin saturation >60% (♂), >50% (♀), ferritin↑↑, HFE mutation ++ (periportal Fe- loaded hepatocytes, quant. liver Fe
Wilson’s Neurological Coeruloplasmin↓, urinary Cu (24h) ↑, slit-lamp: corneal Cu deposits +++ (quant. liver Cu)
α1-Antitrypsin Pulmonary fibrosis α1-AT ↓,
α1-AT subtyping		 +++ (α1-AT-loaded hepatocytes)
Congenital +++ (bile ductular plate malformations etc.)

A1-AT, α1 antitrypsin; AMA, anti-mitochondrial antibodies; ANA, antinuclear antibodies; CDT, carbohydrate deficient transferrin; Cu, copper; Fe, iron; HBV/ HCV/HDV, hepatitis B/C/D virus; HBc/HBe/HBs Ag, hepatitis B core/envelope/surface antigen; LKM, liver kidney membrane; SLA, soluble liver antigen; pANCA, perinuclear neutrophil cytoplasmic antigen.

Treatment of Cirrhosis

Current regimes of antiviral treatment for virus-related cirrhosis

Medicine used Number of patients Virological responses Survival Ref.
HBV-related cirrhosis
ETV (1.0 mg/d) or ADV (10 mg/d) 100 subjects treated with ETV, 91 subjects treated with ADV 57% and 20% of subjects achieve HBV DNA undetectable after 48 wk (ETV and ADV, respectively) Overall 1-yr patient survival rates were 84% and 83% (ETV and ADV, respectively) [83]
TBV (600 mg/d) or LAM (100 mg/d) 114 in the TBV group, another 114 in LAM group 49.1% and 39.5% of subjects achieve HBV DNA undetectable after 104 wk (TBV and LAM, respectively) Overall 1-yr patient survival rates were 94% and 88% (TBV and LAM, respectively) [85]
ETV (0.5 mg/d) 144 compensated and 55 decompensated cirrhosis patients treated with ETV 78.5% and 89.1% of subjects achieve HBV DNA undetectable after 12 mo (compensated and decompensated, respectively) Not analyzed [86]
TDF (300 mg/d) or TDF (300 mg/d) + FTC (200 mg/d) or ETV (0.5 mg/d) 45 in TDF group, 45 in TDF plus FTC group and 22 in ETV group 70.5%, 87.8% and 72.7% achieve HBV DNA undetectable after 48 wk (TDF, TDF plus FTC, ETV, respectively) Not analyzed [84]
ADV (10 mg/d) 226 wait-listed and 241 post-LT patients 59% and 40% achieve HBV DNA undetectable after 48 wk (wait-listed and post transplantation, respectively) Overall 1-yr patient survival rates were 86% and 91% (wait-listed and post transplantation, respectively) [87]
HCV-related cirrhosis
Group 1: PegIFN-2a + RBV2 Group 2: PegIFN-2b + RBV3Group 3: PegIFN-2a + placebo4 453 in group 1, 444 in group 2 and 224 in group 3 69%, 52% and 59% achieve SVR1 after 24 wk (group 1, group 2 and group 3, respectively) Not analyzed [81]
Treated: IFN5Untreated: placebo 72 patients in both treated group and untreated group Not analyzed 5-yr overall survival is 50% and 39% in treated and untreated group, respectively [89]
Non-LT and LT cirrhotic patients are all treated for PEG-IFN a2a or a2b plus RBV6 43 HCV non-LT cirrhotic patients and 17 LT HCV related-cirrhotic patients 69.8% and 47.1% achieve EVR and 41.9% and 29.4% achieve SVR (non-LT group and LT group, respectively) None of the non-LT cirrhotic patients died; LT cirrhotic patients with survival rates of 87% at 1 yr and of 76% at 3 and 5 yr after the treatment

Treatment of Underlying Etiology

  • Alcoholic liver disease is a leading cause of cirrhosis in western countries and, when present, cessation of alcohol use can lead to drastic improvement in ascites and other reversible components of alcoholic liver disease[]. Similarly, the treatment of hepatitis B, hepatitis C, and autoimmune hepatitis can lead to the resolution of ascites or heightened response to medical therapy[].

Bed Rest

  • In theory, upright posture may further aggravate the plasma renin elevation found in patients with cirrhosis and exacerbate salt retention and impairs response to diuretics[,]. However, this theory is not supported by controlled clinical trials and is impractical[]. Thus, bed rest is not advocated as a treatment[].

Salt Restriction

  • Treatment often begins with education regarding dietary sodium restriction[]. Limiting salt intake to 2000 mg/d or 88 mmol/d is often recommended[].
  • Fluid and weight loss are related to sodium balance and more stringent dietary restrictions can speed mobilization of fluid. However, restrictions < 2000 mg/d are not recommended because they are less palatable and create the potential to reduce food intake and worsen the co-existing malnutrition[].
  • In addition, marked reduction in sodium intake does not add efficacy to diuretic treatment, and can lead to increased incidence of diuretic-induced renal failure and hyponatremia[].

Pharmacological Therapy

  • If patients adhere to dietary sodium restriction, one of the goals of treatment is to increase the urinary secretion of sodium to greater than 78 mmol/d[].
  • About 10%-15% of the patient have spontaneous urinary sodium excretion greater than 78 mmol/d, and can be managed with sodium restriction alone[].
  • However, when given a choice, most patients would prefer a combination of diuretics and mild sodium restriction to strict sodium restriction alone[].

First-line diuretics

  • The two most commonly used diuretics in patients with cirrhosis are spironolactone and furosemide[]. Single-agent spironolactone has been shown to be more efficacious than furosemide[].
  • A randomized trial in patients with new onset ascites and well preserved renal function noted slower diuresis and less need for dose adjustment with spironolactone alone, so the authors recommended this approach could be considered appropriate for outpatients[].
  • However, a subsequent study which enrolled patient with long-standing ascites, many of whom with significantly impaired renal perfusion favored use of combination therapy[].
  • Triamterene, metolazone, and hydrochlorothiazide have been successfully used to treat ascites. However, hydrochlorothiazide can result in extreme hyponatremia when added to a combination of spironolactone and furosemide[]. Amiloride (10-40 mg/d) is less efficacious and more expensive when compared to spironolactone, but its use can be justified in patients with tender gynecomastia[]. Other diuretics, such as eplerenone, torasemide, and bumetanide are expensive and have not been extensively studied in the setting of cirrhosis and ascites.

Albumin Infusion

  • An unblinded randomized controlled study showed a mortality benefit in patients with new onset ascites who received weekly 25 g infusions of albumin for one year followed by infusions every other week[].
  • Another trial noted that combination of diuretics and albumin result in higher response rates, shorter hospital stay, lower readmission rates and lower probability of recurrence[]. However, further studies are required before this expensive treatment regimen can be advocated by societies like AASLD.

Transplantation

Liver transplantation[rx]
  • If complications cannot be controlled or when the liver ceases functioning, liver transplantation is necessary. Survival from liver transplantation has been improving over the 1990s, and the five-year survival rate is now around 80%. The survival rate depends largely on the severity of disease and other medical risk factors in the recipient.[rx] In the United States, the MELD score is used to prioritize patients for transplantation.[rx] Transplantation necessitates the use of immune suppressants (ciclosporin or tacrolimus).

Decompensated Cirrhosis

  • Manifestations of decompensation in cirrhosis include gastrointestinal bleeding, hepatic encephalopathy (HE), jaundice or ascites. In patients with previously stable cirrhosis, decompensation may occur due to various causes, such as constipation, infection (of any source), increased alcohol intake, medication, bleeding from esophageal varices or dehydration. It may take the form of any of the complications of cirrhosis listed below.
  • People with decompensated cirrhosis generally require admission to a hospital, with close monitoring of the fluid balance, mental status, and emphasis on adequate nutrition and medical treatment – often with diuretics, antibiotics, laxatives or enemas, thiamine and occasionally steroids, acetylcysteine and pentoxifylline.[rx] Administration of saline is avoided, as it would add to the already high total body sodium content that typically occurs in cirrhosis. Life expectancy without liver transplant is low, at most 3 years.

Palliative care

  • Palliative care is specialized medical care that focuses on providing patients with relief from the symptoms, pain, and stress of a serious illness, such as cirrhosis. The goal of palliative care is to improve quality of life for both the patient and the patient’s family and it is appropriate at any stage and for any type of cirrhosis.[rx]

The speed of Fluid Loss

  • In patients with significant edema, there is no limit to daily weight loss[]. After resolution of edema, daily loss of 0.5 kg is a reasonable maximum. In addition to fluid mobilization, other factors such as serum sodium levels, serum potassium levels, serum creatinine levels, and the presence of clinical complications like HE should guide therapy[].

Utility of Paracentesis

  • Large volume paracentesis is a safe and effective therapy for patients presenting with tense ascites[]. However, this procedure should be followed by sodium restriction and diuretics for patients who are diuretic sensitive.

Refractory ascites

  • Refractory ascites occurs in about 5% of patients with cirrhosis. This condition is defined as ascites that cannot be mobilized despite of sodium restricted diet and high dose diuretics and that accumulates after therapeutic paracentesis[].
  • Medical treatment options remain limited in patients with refractory ascites. Midodrine 7.5 mg three times a day compared to standard therapy has been shown in a pilot randomized control trial of 40 patients followed for a period of three months to increase urine volume, urine sodium, mean arterial pressures, and survival[].
  • The same group in another pilot study compared the combination of midodrine and clonidine to standard therapy and noted an improvement in the above parameters except survival[].

Medications that should be used with caution or avoided

  • NSAIDs can reduce sodium excretion. The AASLD recommends that the use of NSAIDs should generally be avoided in this setting[].
  • Arterial pressure is an independent predictor of survival in a patient with cirrhosis and is dependent on elevated levels of vasopressin, angiotensin, and aldosterone. Therefore, both the European Association for the study of liver and the AASLD recommend against the use of angiotensin-converting inhibitors and angiotensin receptor blockers.

Therapies to Eliminate the Etiological Factors

  • Removing the etiological factors is the most direct and perhaps most effective method of treating liver fibrosis. As such, treatments against HBV and HCV infections[,], abstinence from alcohol abuse, weight and blood lipid control, chelation of overloaded iron and copper[] are considered potentially effective therapies for a large proportion of liver fibrosis cases.
  • In particular, the commonly used antiviral agents such as IFN-α, ribavirin, lamivudine, adefovir, entecavir, and especially pegylated IFN-α have been shown to exert antifibrotic effects[,,–].

Anti-Inflammatory and Immunosuppressive Therapies

  • Intrahepatic inflammation and immune response are direct causes of injury to hepatocytes and activation of HSCs. Therefore, anti-inflammatory and immunosuppressive therapies are important measures to inhibit fibrogenesis, especially for fibrosis and cirrhosis resulting from viral hepatitis, autoimmune hepatitis, and primary sclerosing cholangitis.
  • The anti-inflammatory drug celecoxib[] and antioxidative agents taurine and vitamin E[,] all show some degree of antifibrotic effect. Likewise, glucocorticoids, azathioprine[], colchicines[] and rapamycin[,] appear to exert anti-inflammatory, antifibrotic and immunomodulatory effects, and therefore may potentially be useful in the treatment of liver fibrosis.

Suppressing Activation and Promoting Apoptosis of HSCs

  • HSCs play a critical role in hepatic fibrogenesis, and therefore are potential target cells of antifibrotic therapy[]. As such, inhibition of HSC activation is an attractive therapeutic approach for liver fibrosis. Inactivation of HSCs can be achieved by inhibiting the TGF-β1 signaling pathway and PDGF-B[–], and activated HSCs can be removed by inducing these cells to undergo apoptosis[,,].
  • Some cytokines and growth factors such as insulin-like growth factor-1, IFN-α and IFN-γ have been found to induce apoptosis of HSCs[,,]. Inhibitors of IκB kinase has also been shown to promote apoptosis of HSCs and exert antifibrotic effectd[].
  • Other pharmacological agents such as gliotoxin, sulfasalazine, benzodiazepine ligands, curcumin and tanshinone I have been explored for their effects in inducing HSC apoptosis[].

Protect Liver Function and Promote Hepatocyte Regeneration

  • The hepatoprotective agent silymarin has been widely used in the management of chronic liver diseases and cirrhosis[,]. Ursodeoxycholic acid and tauroursodeoxycholic acid have shown protective effects against hepatocyte organelle injury, and have been confirmed as effective agents for the treatment of primary sclerosing cholangitis[,]. Calcium channel blockers (e.g., verapamil) also show hepatoprotective and antifibrotic effects by stabilizing the hepatic cellular membrane[] and lowering the portal vein pressure.

Gene Therapy and Targeted Therapy

  • Several critical genes implicated in the pathogenesis of liver cirrhosis such as TGF-β, PDGF-β, CTGF, and TIMP have been investigated as therapeutic targets for liver cirrhosis[]. Antisense oligonucleotides[,,] and siRNAs[–] against these genes have been tested in vitro and in vivo.
  • Recently, miRNA has been found to play a regulatory role in the pathogenesis of liver fibrosis and cirrhosis through regulating the expression of profibrotic or antifibrotic genes and influencing the proliferation and activation of HSCs. As such, miRNA-based therapy can potentially be useful for the treatment of liver fibrosis[].
  • Furthermore, in order to target more directly the fibrogenic cells, attempts have been made to target the receptors of the profibrogenic proteins expressed on HSCs[,,].

Complementary and Alternative Medicine

  • Evidence indicates that some traditional Chinese herbal medicines are effective in the treatment of liver fibrosis and cirrhosis, and have thus gained popularity worldwide[,]. These herbal medicines include the following categories: pure compounds (e.g., salvianolic acid B[] and oxymatrine[]).
  • The mechanisms by which tetrandrine[], glycyrrhetinic acid[] and curcumin[]), single agents (e.g., Salvia miltiorrhiza[] and Ganoderma lucidum[]), and composite formulae (e.g., Fuzheng Huayu Capsule[], Biejiajian[], Yi-Gan-Kang granule[] and Qinggan Huoxuefang[]).
  • Chinese herbal medicines exert antifibrotic effect are far from clear but may include antiviral and anti-inflammatory effects, immune regulation, inhibition of HSC activity, and promotion of collagen degradation. Further randomized controlled clinical trials are needed and the possible adverse effects should be carefully evaluated.

Complications

Ascites

  • Salt restriction is often necessary, as cirrhosis leads to accumulation of salt (sodium retention). Diuretics may be necessary to suppress ascites. Diuretic options for inpatient treatment include aldosterone antagonists (spironolactone) and loop diuretics. Aldosterone antagonists are preferred for people who can take oral medications and are not in need of an urgent volume reduction. Loop diuretics can be added as additional therapy.[rx]
  • If a rapid reduction of volume is required, paracentesis is the preferred option. This procedure requires the insertion of a plastic tube into the peritoneal cavity. Human albumin solution is usually given to prevent complications from rapid volume reduction. In addition to being more rapid than diuretics, 4–5 liters of paracentesis is more successful in comparison to diuretic therapy.[rx]

Esophageal Variceal Bleeding

  • For portal hypertension, nonselective beta blockers such as propranolol or nadolol are commonly used to lower blood pressure over the portal system. In severe complications from portal hypertension, transjugular intrahepatic portosystemic shunting (TIPS) is occasionally indicated to relieve pressure on the portal vein.
  • As this shunting can worsen hepatic encephalopathy, it is reserved for those patients at low risk of encephalopathy. TIPS is generally regarded only as a bridge to liver transplantation or as a palliative measure.

Hepatic Encephalopathy

  • High-protein food increases the nitrogen balance, and would theoretically increase hepatic encephalopathy; in the past, this was therefore eliminated as much as possible from the diet. Recent studies show that this assumption was incorrect, and high-protein foods are even encouraged to maintain adequate nutrition.[rx]

Hepatorenal Syndrome

  • The hepatorenal syndrome is defined as urine sodium less than 10 mmol/L and serum creatinine > 1.5 mg/dl (or 24-hour creatinine clearance less than 40 ml/min) after a trial of volume expansion without diuretics.[rx]

Spontaneous Bacterial Peritonitis

  • People with ascites due to cirrhosis are at risk of spontaneous bacterial peritonitis.

Portal Hypertensive Gastropathy

  • This refers to changes in the mucosa of the stomach in people with portal hypertension, and is associated with cirrhosis severity.[rx]

Infection

  • Cirrhosis can cause immune system dysfunction, leading to infection. Signs and symptoms of infection may be nonspecific and are more difficult to recognize (for example, worsening encephalopathy but no fever).

Hepatocellular Carcinoma

  • Hepatocellular carcinoma is a primary liver cancer that is more common in people with cirrhosis. People with known cirrhosis are often screened intermittently for early signs of this tumor, and screening has been shown to improve outcomes.[rx]

Varices and Portal Hypertension

  • These are large, swollen veins in the esophagus and stomach. They can increase pressure in a blood vessel called the portal vein that carries blood from the spleen and bowel to the liver. Varices can rupture, causing severe blood loss and clots.

Hepatic Encephalopathy

  • This refers to high levels of toxins in the blood where the liver is no longer successfully filtering them all.

Hepatocellular Carcinoma 

  • This is the most common type of liver cancer. It is the third-leading cause of cancer mortality across the globe.

Hepatopulmonary Syndrome (HPS) 

  • Doctors define HPS as a combination of liver disease, dilated blood vessels in the lungs, and abnormalities in the exchange of gases. It is linked to an increase in the mortality rate of people waiting for a liver transplant.

Coagulation Disorders

  • Cirrhosis can cause problems with blood clotting, leading to potentially fatal bleeds and clots.

Other complications from cirrhosis include:

  • bruising (due to low platelet count and/or poor clotting)
  • bleeding (due to decreased clotting proteins)
  • sensitivity to medications (the liver processes medications in the body)
  • kidney failure
  • liver cancer
  • insulin resistance and type 2 diabetes
  • hepatic encephalopathy (confusion due to the effects of blood toxins on the brain)
  • gallstones (interference with bile flow can cause bile to harden and form stones)
  • esophageal varices
  • enlarged spleen (splenomegaly)
  • edema and ascites

Indications and contraindications for orthotopic liver transplantation

INDICATIONS
Advanced Chronic Liver Failure
  • – CPT score > 7
  • – Qualifying MELD Score for Organ Allocation
Acute Liver Failure
  • Unresectable Hepatic Malignancy
  • Inherited Metabolic Disorders
General
  • No alternative form of therapy
  • No absolute contraindications
  • Willingness to comply with follow up care
  • Ability to provide for costs of OLT
CONTRAINDICATIONS
Relative
  • HIV seropositivity
  • Methadone dependence
  • Stage 3 HCC

*
Absolute
  • Extrahepatic malignancy
  • AIDS
  • Cholangiocarcinoma
  • Severe, uncontrolled systemic infection
  • Multiorgan failure
  • Advanced cardiopulmonary disease
  • Active substance abuse

References

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Cirrhosis

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