Disorders of the liver

Jaundice

Jaundice occurs when the serum bilirubin level is elevated above 3 mg/dl. Clinical signs include yellowing of the sclera and skin. Symptoms vary depending on the cause, including loss of appetite, arthralgia, itching, rashes, nausea and vomiting, myalgia, and fever. Unconjugated or indirect bilirubin is insoluble in water but is soluble in lipids. So it can easily cross across lipid-rich cell membranes. It is transported in serum and bound to albumin. Bilirubin is conjugated in the liver by the enzyme glucuronyl transferase. Conjugated or direct bilirubin is water soluble.

Conjugated hyperbilirubinemia

Conjugated hyperbilirubinemia results from disorders primarily affecting the liver, like hepatitis or extrahepatic cholestasis caused by biliary strictures, masses obstructing the common bile duct, etc.

Common causes of conjugated hyperbilirubinemia

• Hepatitis: viral (Hep A, B, C), alcoholic or autoimmune
• Sepsis
• Fatty liver
• Pregnancy
• Drug-induced hepatitis (acetaminophen, aspirin, isoniazid, phenytoin, some herbal remedies, and supplements, etc.)
• Drug-induced cholestasis (e.g. anabolic steroids, estrogens, chlorpromazine, OCpills)
• ABO incompatibility
• Dubin Johnson syndrome
• Rotor’s syndrome
• Primary biliary cirrhosis
• Primary sclerosing cholangitis
• Wilson’s disease, hemochromatosis
• Malignancies
• Gallstones
• Carcinoma head of pancreas
• Biliary stricture or atresia
• Cystic fibrosis
• TORCH infections in newborn
• Galactosemia, tyrosinosis

Unconjugated hyperbilirubinemia

Unconjugated hyperbilirubinemia results from excessive RBC breakdown that overwhelms the conjugating capacity of the liver or disorders in the conjugating capacity of the liver as seen in newborns and Gilbert syndrome etc. Imaging studies help to arrive at the underlying cause. Ultrasound and CT scans help with parenchymal liver and gallbladder disorders, while ERCP and MRCP are used to detect intrahepatic and extrahepatic biliary tree lesions. Endoscopic ultrasound helps visualize what type of lesion obstructs the biliary tree. A liver biopsy can help to confirm hepatic parenchymal disorders. Autoimmune antibodies are detected in serological studies of autoimmune hepatitis.

Common causes of unconjugated hyperbilirubinemia

• Hemolytic anemias
• Criggler Najjar syndrome
• Gilbert syndrome
• RBC enzyme deficiencies e.g. G6PD, pyruvate kinase
• Polycythemia vera
• Neonatal physiologic jaundice
• Breast milk jaundice
• Pyloric stenosis
• Cephalhematoma

Laboratory findings in jaundice

Elevated AST (SGOT) and ALT (SGPT) indicate liver dysfunction, but can be normal or even low with loss of liver parenchymal tissue in cirrhosis . Levels of AST and ALT can reach >10,000 U/L in hepatic injury from drugs like acetaminophen or ischemia. Hepatic causes of elevated alkaline phosphatase are biliary obstruction and parenchymal liver disease. Gamma glutamyl transferase is elevated in biliary obstruction and alcoholic liver disease.

In alcoholic hepatitis, the ratio AST>ALT, while in infectious hepatitis ALT>AST

Dubin Johnson syndrome

It is a hereditary conjugated hyperbilirubinemia seen in Iranian and Moroccan Jews living in Israel and the Japanese population. It is AR. Dubin Johnson syndrome is caused by mutations in the ABCC2 gene that codes for the protein MRP2 or multidrug resistance associated protein 2. This mutation leads to decreased transport of bilirubin and some other molecules across the hepatocytes into the bile canaliculi. It presents with jaundice, fatigue, abdominal pain, nausea, vomiting, hepatomegaly, and conjugated hyperbilirubinemia. The liver looks black due to the accumulation of epinephrine metabolites. In asymptomatic women with Dubin Johnson syndrome, pregnancy or OC pill use may precipitate symptoms. Patients do well even without any specific treatment. Medications with hepatotoxicity should be taken under careful medical supervision.

Rotor syndrome

It is an AR, inherited cause of hyperbilirubinemia caused by mutations in the SLCO1B1 and SLCO1B3 genes which code for organic anion transporting polypeptide 1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3), respectively. This leads to a defect in transporting bilirubin from the blood to the hepatocytes. It presents with mild, recurrent jaundice. Both conjugated (++) and unconjugated bilirubin (+) levels are elevated. Rotor syndrome is considered a benign disorder and does not require treatment.

Gilbert syndrome

It is a common inherited AR or AD disorder that causes unconjugated hyperbilirubinemia. It is caused by mutations in the UGT1A1 gene that codes for the enzyme bilirubin uridine diphosphate glucuronyl transferase (bilirubin UGT) that converts unconjugated bilirubin to conjugated bilirubin. Patients have reduced activity of the enzyme. Different types of mutation are seen, many being in the promoter region of the gene. Jaundice may not always be present, but hyperbilirubinemia can be seen on serological testing under certain conditions such as dehydration, vigorous exercise, fasting, illness, alcohol, or menstruation. Most people are asymptomatic. No specific treatment is needed. Some patients may develop diarrhea after administration of irinotecan.

Criggler Najjar syndrome

It is a rare, AR inherited cause of unconjugated hyperbilirubinemia caused by mutations in the UGT1A1 gene that codes for the enzyme bilirubin uridine diphosphate glucuronosyl transferase (bilirubin-UGT) (same gene as Gilbert syndrome). This affects the conjugation or glucuronidation of bilirubin to form conjugated bilirubin. There are two types of Criggler-Najjar syndrome - types 1 and 2. Type 1 is more severe, with a total absence of enzyme function, while type 2 has about 20% enzyme function. It presents with jaundice, kernicterus (more common in type 1) and unconjugated hyperbilirubinemia. Patients may develop bilirubin encephalopathy during illness, prolonged fasting, or under anesthesia. Phototherapy is used to correct acute episodes of hyperbilirubinemia. Type 2 may also respond to phenobarbital, while type 1 does not. Exposure to sunlight helps in reducing mild elevations in bilirubin levels. Plasmapheresis can remove unconjugated bilirubin and can be used in addition to phototherapy. Liver transplantation is the only definitive treatment for type 1 disease.

Autoimmune hepatitis or AIH

It is inflammation of the liver that can progress to cirrhosis, seen in autoimmune disorders like SLE, Hashimoto’s thyroiditis, etc. It is more common in women. It presents with fatigue, nausea, loss of appetite, jaundice, pruritus, arthralgia, and signs of cirrhosis in advanced cases. Laboratory findings include elevated AST and ALT, IgG, gamma globulins, ANA, anti-smooth muscle antibodies, and anti-LKM1 (liver-kidney microsomal) antibodies. HLA DR3 and DR4 may be positive. Liver biopsy shows typical features of inflammation and cirrhosis in severe cases. It responds to corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine, or tacrolimus. Maintenance therapy is with prednisone or azathioprine. A liver transplant may be needed.

Non-alcoholic fatty liver or steatohepatitis

It is seen in middle-aged, overweight, or obese individuals with metabolic syndrome and insulin resistance, prediabetes, diabetes, or elevated cholesterol and triglycerides in their blood. Some children may be affected. It is characterized by lipid accumulation in the hepatocytes and is not caused by alcohol. In fatty liver, the liver contains more than 5-10% fat.

Variations in the PNPLA3 gene that codes for adiponutrin ( a lipase), leading to increased lipid production and decreased lipolysis has been implicated. Activation and recruitment of inflammatory cells and activation of stellate cells that secrete collagen, resulting in fibrosis. Increased production of reactive oxygen species occurs due to uncoupling of oxidative phosphorylation, causing more hepatocyte damage. Endotoxins may activate Kupffer cells via Toll Like Receptors TLR2 and 4, leading to increased synthesis of TNF alpha and IL1. Increased lipolysis of adipose tissue releases more free fatty acids, which are converted and stored in the liver as triglycerides.

Most patients are asymptomatic. Some may present with fatigue, abdominal pain, mild hepatomegaly and signs of cirrhosis in severe cases. Once inflammation develops, 30% cases progress to cirrhosis. There is also increased risk of hepatocellular carcinoma. Biopsy findings include typical changes of fatty liver, ballooning degeneration and perivenular and perisinusoidal fibrosis with inflammatory infiltrate. Mallory bodies may be seen. Classically, the lipid in NAFLD accumulates around the central vein (zone 3) in adults, but as the disease progresses, it may show a panlobular distribution involving all zones. Laboratory findings include elevated AST and ALT. Management is by weight reduction, healthy eating, increasing physical activity, avoiding hepatotoxic agents like alcohol and certain medications. Treating insulin resistance with metformin, rosiglitazone and pioglitazone helps. Antioxidants like vitamin E, selenium and betaine may also help.