Chronic Liver Disease – Causes, Symptoms, Treatment

Chronic Liver Disease (CLD) is a progressive deterioration of liver functions for more than six months, which includes synthesis of clotting factors, other proteins, detoxification of harmful products of metabolism and excretion of bile. CLD is a continuous process of inflammation, destruction, and regeneration of liver parenchyma, which leads to fibrosis and cirrhosis. The spectrum of etiologies is broad for chronic liver disease, which includes toxins, alcohol abuse for a prolonged time, infection, autoimmune diseases, genetic and metabolic disorders. Cirrhosis is a final stage of chronic liver disease that results in disruption of liver architecture, the formation of widespread nodules, vascular reorganization, neo-angiogenesis, and deposition of an extracellular matrix. The underlying mechanism of fibrosis and cirrhosis at a cellular level is the recruitment of stellate cells and fibroblasts, resulting in fibrosis, while parenchymal regeneration relies on hepatic stem cells. Chronic liver disease is an extremely common clinical condition, and the focus is done on the common etiologies, clinical manifestations, and management.

Causes of Chronic Liver Disease

The following are the most common etiologies

• Alcoholic Liver Disease – Alcoholic liver disease is a spectrum of disease which includes alcoholic fatty liver with or without hepatitis, alcohol hepatitis (reversible because of acute ingestion) to cirrhosis (irreversible). Patients with severe alcohol use disorder mostly develop the chronic liver disease; this is the most frequent cause of CLD.
• Non-alcoholic Fatty Liver Disease (NAFLD/NASH) – NAFLD has an association with metabolic syndrome (obesity, hyperlipidemia, and diabetes mellitus). Some of these patients develop non-alcoholic steatohepatitis, which leads to fibrosis of the liver. All the risk factors of metabolic syndrome can aggravate the disease process.
• Chronic Viral Hepatitis – Chronic hepatitis B, C, and D infections are the most common causes of chronic liver disease in East Asia and Sub-Saharan Africa. There are various genotypes of hepatitis C. In Europe and North America, genotype 1a and 1b are more prevalent, while in Southeast Asia, genotype 3 is more common. A molecular epidemiological study revealed a high prevalence of HCV genotype 4, subtype 4a among Egyptian patients living in Sharkia governorate, Egypt. Chronic hepatitis C, if not treated, may lead to hepatocellular carcinoma.

Genetic Causes

• Alpha-1 antitrypsin deficiency – This is the most common genetic cause of CLD among children.
• Hereditary hemochromatosis – It is an autosomal recessive disorder of iron absorption. Here due to a mutation involving the HFE gene that regulates the iron absorption from the intestine, excessive iron is absorbed from the gastrointestinal tract. As a result, there is a pathological increase in total body iron (such as ferritin and hemosiderin). This process leads to the generation of hydroxyl free radicals, which in turn causes organ fibrosis.
• Wilson disease – Autosomal recessive disorder leading to copper accumulation

Autoimmune Causes

Autoimmune hepatitis is a rare disease in which there is the destruction of liver parenchyma by autoantibodies. Most of the patients who present with this disease have already developed cirrhosis. Females are more commonly affected than males.

• Primary biliary cirrhosis (PBC) – This is an autoimmune and progressive disease of the liver, which is the destruction of intrahepatic biliary channels and portal inflammation and scarring. It leads to cholestatic jaundice and fibrosis of liver parenchyma. PBC is more common in middle-aged women. Alkaline phosphatase levels increase in PBC.
• Primary Sclerosing Cholangitis (PSC) – commonly associated with ulcerative colitis. This condition is characterized by a decrease in the size of intrahepatic and extrahepatic bile ducts due to inflammation and fibrosis.
• Autoimmune hepatitis (AIH) – This is a form of chronic inflammatory hepatitis, more common in women than men, and is characterized by elevated autoantibodies such as antinuclear antibodies, anti-smooth muscle antibodies, and hypergammaglobulinemia.

Other Causes of Chronic Liver Disease

• Drugs – amiodarone, isoniazid, methotrexate, phenytoin, nitrofurantoin.
• Vascular. Budd-Chiari syndrome.
• Idiopathic/cryptogenic, around 15%

Viral causes

• Hepatitis B
• Hepatitis C

Cytomegalovirus (CMV), Epstein Barr virus (EBV), and yellow fever viruses cause acute hepatitis.

Toxic and drugs

• Alcoholic liver disease
• Rarely drug-induced liver disease from methotrexate, amiodarone, nitrofurantoin, and others

Paracetamol (acetaminophen) causes acute liver damage.

Symptoms of Chronic Liver Disease

Signs of chronic liver disease detectable on clinical examination can be divided into those that are associated with the diagnosis of chronic liver disease, associated with decompensation and associated with the cause.

Chronic liver disease

• Nail clubbing
• Palmar erythema
• Spider nevi (angiomata)
• Gynaecomastia
• Feminizing hair distribution
• Testicular atrophy
• Small irregular shrunken liver
• Anemia
• Caput medusae

Decompensation

• Drowsiness (encephalopathy)
• Hyperventilation (encephalopathy)
• Metabolic flap/asterixis (encephalopathy)
• Jaundice (excretory dysfunction)
• Ascites (portal hypertension and hypoalbuminemia)
• Leukonychia (hypoalbuminemia)
• Peripheral edema (hypoalbuminemia)
• Bruising (coagulopathy)
• Acid-base imbalance, most commonly respiratory alkalosis

Signs associated with the cause

• Dupuytren’s contracture (alcohol)
• Parotid enlargement (alcohol)
• Peripheral neuropathy (alcohol and some drugs)
• Cerebellar signs (alcohol and Wilson’s disease)
• Liver enlargement (alcohol, NAFLD, haemochromatosis)
• Kayser-Fleisher rings (Wilson’s disease)
• Increased pigmentation of the skin (haemochromatosis)
• Signs of right heart failure

Others Symptoms may include

• Fluid buildup in the belly (ascites)
• Vomiting blood, often from bleeding in the blood vessels in the food pipe (esophagusGallstones
• Itching
• Yellowing of the skin and eyes (jaundice)
• Kidney failure
  Muscle loss
• Loss of appetite
• Easy bruising
• Spider-like veins in the skin
• Low energy and weakness (fatigue)
• Weight loss
• Confusion as toxins build up in the blood

Diagnosis of Chronic Liver Disease

Clinical Manifestations – Signs and symptoms of CLD can be nonspecific, such as fatigue, anorexia, weight loss, or depend upon the complication that the patient has developed. The three significant complications are because of portal hypertension (esophageal varices, ascites), hepatocellular insufficiency (e.g., jaundice, hepatic encephalopathy), and hepatocellular carcinoma. Decompensated chronic liver disease can present with one of the following complications.

Portal Hypertension – Portal hypertension is a result of resistance to portal blood flow because of cirrhotic and noncirrhotic etiology. A portal venous pressure above seven mmHg is considered as portal hypertension; however, clinical features or complications do not develop until portal pressure is higher than 12 mmHg. Portal hypertension causes can divide into prehepatic (e.g., portal vein thrombosis), hepatic (e.g., cirrhosis), and post hepatic (e.g., Budd Chiari syndrome). Cirrhosis and hepatic schistosomiasis remain the most common cause of portal hypertension, with cirrhosis being more common in developed countries. The following are the consequences of long-standing portal hypertension.

• Esophageal varices – It presents with melena or upper GI bleed. Cirrhosis of the liver leads to raised portal pressure, which can cause esophageal or gastric varices. Esophageal variceal bleeding is the most common life-threatening complication of CLD.
• Caput medusae
• Rectal hemorrhoids
• Ascites – It is an accumulation of fluid in the peritoneal cavity because of raised portal pressure (increased hydrostatic pressure), decreased albumin (reduced oncotic pressure), and splanchnic vasodilation (due to the release of nitric oxide). Most of the patients develop ascites in the later stages of cirrhosis. Clinical findings in such patients are abdominal distension, shifting dullness, and a fluid wave. Tense ascites can lead to shortness of breath or early satiety.

Hepatocellular Insufficiency

Hepatic encephalopathy – This is a neuropsychiatric syndrome caused by hepatic dysfunction. Detoxification of harmful products of metabolism, e.g., ammonia, occurs in the liver. In the patient with cirrhosis, the removal of these substances from the body is impaired, leading to an increased level of ammonia. Raised levels of ammonia can impair consciousness. Almost 50% of patients with DCLD can develop hepatic encephalopathy.

According to AASLD guidelines, depending upon the severity of the disease, there are different grades of hepatic encephalopathy.[rx]

• Grade 0/Minimal – Subclinical, normal mental status with minimal changes in memory, coordination, intellectual function, concentration.
• Grade 1 – Trivial lack of awareness, euphoria or anxiety, shortened attention span, impairment of addition or subtraction, altered sleep rhythm.
• Grade 2 – Lethargy or apathy, disorientation to time, personality change, inappropriate behavior, dyspraxia, asterixis.
• Grade 3 – Somnolence to semi-stupor, responsive to stimuli, confused, gross disorientation, bizarre behavior.
• Grade 4 – Coma

The patient can present in any of these symptoms. Most of the patients with hepatic encephalopathy present with altered sensorium. Infections, GI bleed, hyperkalemia, TIPS[rx], sedating agents, and alkalosis can aggravate hepatic encephalopathy.

Jaundice

Jaundice is a yellowish discoloration of eyes, skin, and mucous membrane because of overproduction or under clearance of bilirubin. Metabolism of hemoglobin or myoglobin produces bilirubin in the spleen. Bilirubin then circulates in the body, bound to albumin. The liver dissociates this complex and converts unconjugated bilirubin to conjugated bilirubin. Jaundice is clinically visible when total bilirubin is greater than 2 mg/dl. As in chronic liver disease, there is the destruction of liver parenchyma, and it does not conjugate bilirubin, which deposits in various tissues of the body. There is pruritus because of the accumulation of bile salts.

Spontaneous Bacterial Peritonitis (SBP)

It is one of the acute and painful complications of chronic liver disease. Bacteria (E. coli, Klebsiella, Streptococcus pneumonia) seep through the gastrointestinal tract and infect the ascitic fluid. The infection spread through the fluid to the peritoneal membrane, causing inflammation. SBP presents with fever, generalized abdominal pain, tenderness, and absent bowel sounds.

Hyperestrinism

In chronic liver disease, the catabolism of estrogen becomes impaired, resulting in excess estrogen in the body. This manifests as palmar erythema, spider angiomas (dilated cutaneous arterioles with a central red spot and red extensions that radiate outward like a spider’s web in the territory of SVC), gynecomastia (enlarged tender subareolar tissue) and testicular atrophy.

Hepatorenal Syndrome (HRS)

Hepatorenal syndrome is a functional renal failure as kidneys are normal, where there is a gradual loss of renal function. It is a diagnosis of exclusion. Vasoconstrictors are released in CLD, which is responsible for the narrowing of renal vessels. The following criteria have been described:

• Chronic liver disease with portal hypertension or advanced liver failure
• Continuous rising in creatinine, usually more than 0.3 mg/dl within 48 hours or doubling from baseline within seven days.
• Oliguria with the absence  or minimal proteinuria
• Urine sodium less than 10 meq/L
• Failure to improve with volume expansion and stopping the diuretics.
• Absence of shock
• No recent use of the nephrotoxic drug
• Absence of renal parenchymal disease

Coagulopathy

• The liver produces clotting factors, so the patients with CLD have coagulopathies and manifest or contribute to easy bruising and bleeding per gastrointestinal tracts. Hence, PT/INR (intrinsic pathway) and APTT (extrinsic pathways) are prolonged.

Evaluation

The diagnosis of chronic liver disease depends upon the etiology and complications of the disease. An outline regarding the diagnosis for various CLD appears below.

• Viral hepatitis B and C – Serology, PCR (quantitative and qualitative) with genotype
• Alcoholic liver disease – Elevated levels of AST>ALT with a history of chronic alcohol intake. Usually, AST: ALT ratio is 2 to 1 in alcoholic liver disease.
• Hemochromatosis – Raised serum iron, ferritin, decreased TIBC, and liver biopsy. Genetic testing can detect a mutation in the HFE gene, especially C282Y.
• Wilson disease – Raised urine copper, decreased serum ceruloplasmin, and liver biopsy. Genetic testing for the ATP7B gene.
• Non-alcoholic fatty liver disease – Diagnosis of exclusion and ALT>AST. Ultrasonography of the liver is informative.
• Autoimmune hepatitis – Raised ANA, ASMA, and LKM-1
• Alpha 1 antitrypsin deficiency – Decreased levels of alpha one antitrypsin
• Primary biliary cirrhosis – Markedly raised alkaline phosphatase levels with an antimitochondrial antibody
• Budd-Chiari and venous-occlusive disease – CBC, clotting profile, and imaging studies like ultrasound doppler or computed tomography with contrast study

Radiologic Investigations

It includes an abdominal ultrasound, CT scan, fibro scan, hepatic wedge pressure, endoscopy, EEG, TIPS, triphasic CT, and Doppler scan.

• Ultrasound abdomen – is one of the most common and affordable imaging studies in a case of chronic liver disease. Ultrasound detects the size, echogenicity nodularity of the liver, thereby diagnosing liver cirrhosis. Other benefits of ultrasound in CLD include measurement of portal vein diameter as portal vein diameter increases in portal HTN and assessment of a clot in the hepatic vein (Budd-Chari) and portal vein in portal vein thrombosis.
• Computed tomography – scan can show a lesion in the liver or obstruction of biliary channels in a more precise way, but triphasic CT is the test of choice in diagnosing hepatocellular carcinoma.
• Transient elastography (TE) –  detects early stages of cirrhosis. It can also detect cardiovascular damage in patients with NAFLD.[rx] It works on two physical principles; strain displacement and shear wave imaging and quantification. The latter includes point shear wave elastography. It measures the velocity of low frequency (50 Hz) elastic shear wave propagating through the liver. The stiffer the tissue, the faster elastic shear wave propagates. It can easily work on an ultrasound machine. According to the European association of study for the Liver (EASL), TE is the most effective approach to diagnose cirrhosis in chronic liver disease.
• Wedged hepatic venous pressure – measures portal venous pressure in CLD.
• Doppler scan – can help in diagnosing Budd-Chiari and portal vein thrombosis.
• EEG – shows delta waves in hepatic encephalopathy.
• An upper endoscopy – can diagnose and treat esophageal varices. On endoscopy, we can measure the size of varices. Small varices are less than 5 mm, and large varices are greater than 5 mm.
• A liver biopsy – can confirm the diagnosis of chronic liver disease. Various techniques to perform a liver biopsy are laparoscopic, transjugular, or percutaneously.

Treatment of Chronic Liver Disease

Prevention of Precipitating Factors Leading to Acute Hepatic Decompensation

• To have a high degree of suspicion, evaluate and treat any infection as early as possible.
• Attain sustained viral suppression of HBV and HCV
• Intravenous administration of albumin in patients with diagnosed spontaneous bacterial peritonitis to prevent accelerated renal dysfunction characterized by hepatorenal physiology. Intravenous albumin has no proven benefit in other bacterial infections
• Prophylactic antibiotics for low ascetic albumin
• In patients with severe acute alcoholic hepatitis, early initiation of both Pentoxifylline or a combination of prednisolone and intravenous N-acetylcysteine has shown to reduce the incidence of type-1 hepatorenal syndrome.
• In patients with severe sepsis, a combination of granulocyte colony-stimulating factor (C-CSF) and Darbepoetin has shown to have improved 1-year survival in decompensated cirrhotics.

Supportive Care

• Access hemodynamic stability and the need for intravenous fluids and maintenance of acid-base levels and normal electrolytes. Vasopressors are indicated to maintain a mean arterial pressure of greater than or equal to 75 mm Hg to ensure adequate renal and cerebral perfusion.
• Monitor hematocrit for any bleeding, as the patients have coagulopathy and poor platelet functions. Blood products of platelets and fresh frozen plasma for coagulopathy is only indicated in patients with active bleeding or before an invasive procedure. Patients should be empirically started on proton pump inhibitors for prophylaxis of gastrointestinal bleed.
• Monitor hepatic encephalopathy and protect airway (aspiration risk) should the patient show signs of worsening encephalopathy. This patient should be intubated and should be on a protocol to avoid cerebral edema.
• Adequate nutrition with 1.0 to 1.5 gm of protein per kilogram per day should be administered
• Monitor for hypoglycemia and maintain blood glucose between 160 to 200.
• Discontinue all home medications except the ones we identify essential to continue.

Specific Treatment when Etiology is Known

• Patients with hepatitis A and E associated ACLF should receive supportive care as no specific anti-virals are known to be effective.
• Patients with acute or reactivation of hepatitis C should receive appropriate anti-virals based on prior treatment administered
• Patients with acute or reactivation of hepatitis B should receive nucleos(t)ide analogues.
• Patients with acute decompensation in known Wilson’s disease or development of hepatic vein thrombosis as the etiology for ACLF should be considered for a liver transplant.

Treatment and Prophylaxis

The treatment goal is to stop the progression of the disease and complications and require a multidisciplinary approach. The principle of management is mainly underlying cause correction, Portal hypertension management, and specific treatments for individual disease. A brief outline regarding treatment for various CLD and related complications is given below. For more comprehensive details, please see individual topics in the Statpearls glossary.

General Management

Patients of chronic liver disease mostly present with one of the complications.

Esophageal varices – Varices related bleeding are one of the deadly complications, and the treatment includes aggressive fluid resuscitation, vasopressors (octreotide, terlipressin), and endoscopy. Endoscopic band ligation and injection sclerotherapy are the usual modalities to treat variceal bleed in an emergency. In some patients, early transjugular intrahepatic portosystemic shunt (TIPS) can increase the survival rate. Propranolol is used for primary and secondary prophylaxis for esophageal varices. Diuretics (furosemide, spironolactone) and sodium restriction are essential treatment options for ascites. For tense ascites, therapeutic paracentesis is done. Albumin infusion can also be considered. Initially, broad-spectrum antibiotics are the treatment of choice for SBP and then specific antibiotics after culture.

Hepatic encephalopathy – The basic principle of treatment is to address the precipitating factors. Patients with hepatic encephalopathy usually improve with precipitating cause correction along with rifaximin and lactulose.[rx][rx] Lactulose acts by converting ammonia to ammonium ion and decreases its absorption from the gastrointestinal tract. Lactulose also relieves constipation through its osmotic effect, which further helps to ease the symptoms of hepatic encephalopathy. Rifaximin is used to decrease ammonia production by gut flora. Liver transplant is the curative treatment in patients with hepatorenal syndrome.

Hepatorenal syndrome – HRS based on severity divided into two categories. HRS 1 is more severe compared to HRS 2 (less severe). The primary goal is to correct underlying cause correction to reverse acute kidney injury. Treatment modalities depend on the severity and location of the patient. Treatment modalities include norepinephrine or terlipressin with albumin infusion or midodrine, octreotide with albumin infusion. TIPS procedure in some patients can help and liver transplantation the only definite treatment in the patient who fails to respond to all other treatments.[rx][rx][rx]

Hepatocellular carcinoma (HCC) – Treatment is based on the Barcelona clinic liver cancer staging system in the management of HCC:

• Initial stage (single HCC lesion): Resection and ablation.
• Intermediate stage: Transarterial chemoembolization and radio-embolization.[rx]
• Metastatic disease: Sorafenib[rx]

Specific Treatment

Viral Hepatitis

• Continuous viral suppression with nucleoside and nucleotide analogs
• Direct-acting antivirals achieving HCV eradication
• Interferon-alpha

Alcoholic liver disease – Alcohol abstinence

Non-alcoholic fatty liver disease – Treatment of metabolic syndrome components

Autoimmune hepatitis – Corticosteroids and other immunosuppressive drugs

Hereditary hemochromatosis – Phlebotomy, iron-chelators

Copper overload (Wilson disease) – Copper chelators

Alpha-1-antitrypsin deficiency – Transplant

Drugs and toxins – Identify and stop the factor

Primary biliary cholangitis (PBC) – Ursodeoxycholic acid (UDCA)[rx]

Primary sclerosing cholangitis – Transplant

Budd-Chiari syndrome – Anticoagulation, thrombolysis or angioplasty with or without stenting, TIPS, or liver transplant

Complications

• Cerebral edema – Encephalopathy: Is usually classified based on the severity from grade 1 to grade 4.

  • Grade 1: change of mood, inappropriate behavior, attention deficit, difficulty in elaborating ideas, irritability, sleep-disordered.
  • Grade 2: temporary disorientation, lethargy, or asterixis.
  • Grade 3: marked confusion, unintelligible speech, somnolence.
  • Grade 4: coma, unresponsive to a verbal or painful stimulus.
• Intracranial pressure – above 20 mm Hg usually correlates with cerebral edema. It can progress to intracranial hypertension. It is present in 75% to 80% of patients with ALF and grades 4 hepatic encephalopathies. The first signs suggestive of intracranial hypertension are systolic hypertension and bradycardia.
• Coagulopathy – The most common site of bleeding is from the upper gastrointestinal tract.
• Hematologic manifestations – Hepatitis-associated aplastic anemia (HAA) is a rare but life-threatening condition.
• Infection – Due to a decrease in immunity, ALF patients predispose to multiple infections, which is the leading cause of mortality. Bacterial infections are responsible for 80%, and about 20 to 30% are fungal infections. When ascites is present, unexplained fever and leukocytosis are indications for a diagnostic paracentesis. Prophylactic antibiotics are not a current recommendation.
• Renal failure – Acute renal failure is frequently a complication and is usually the result of hemodynamic alterations. It represents a poor prognosis. The most critical associated entities are hypovolemia, low systemic vascular resistance, acute tubular necrosis, gastrointestinal blood loss, and hepatorenal syndrome.
• Nutritional and metabolic – Due to the high catabolic state of ALF, maintaining adequate nutrition is vital. Early enteral or parenteral feeds should be initiated. Electrolyte abnormalities such as hyponatremia, hypokalemia, hypophosphatemia, hypomagnesemia, and acid-base imbalances such as respiratory acidosis are frequent. Hyponatremia is an indicator of poor prognosis.
• Pulmonary complications – Pulmonary edema, pneumonia, and tracheobronchitis are the main complications.[rx]

Prevention

To prevent liver disease

• Drink alcohol in moderation – For healthy adults, that means up to one drink a day for women and up to two drinks a day for men. Heavy or high-risk drinking is defined as more than eight drinks a week for women and more than 15 drinks a week for men.
• Avoid risky behavior – Use a condom during sex. If you choose to have tattoos or body piercings, be picky about cleanliness and safety when selecting a shop. Seek help if you use illicit intravenous drugs, and don’t share needles to inject drugs.
• Get vaccinated – If you’re at increased risk of contracting hepatitis or if you’ve already been infected with any form of the hepatitis virus, talk to your doctor about getting the hepatitis A and hepatitis B vaccines.
• Use medications wisely – Take prescription and nonprescription drugs only when needed and only in recommended doses. Don’t mix medications and alcohol. Talk to your doctor before mixing herbal supplements or prescription or nonprescription drugs.
• Avoid contact with other people’s blood and body fluids – Hepatitis viruses can be spread by accidental needle sticks or improper cleanup of blood or body fluids.
• Keep your food safe – Wash your hands thoroughly before eating or preparing foods. If traveling in a developing country, use bottled water to drink, wash your hands and brush your teeth.
• Take care with aerosol sprays – Make sure to use these products in a well-ventilated area, and wear a mask when spraying insecticides, fungicides, paint and other toxic chemicals. Always follow the manufacturer’s instructions.
• Protect your skin – When using insecticides and other toxic chemicals, wear gloves, long sleeves, a hat and a mask so that chemicals aren’t absorbed through your skin.
• Maintain a healthy weight – Obesity can cause nonalcoholic fatty liver disease.

References