Disorders of the Hepatobiliary System

Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). Hepatitis C virus is an RNA virus and a member of the genus Hepacivirus and the family Flaviviridae. The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C virus can cause both acute and chronic hepatitis, ranging from a mild to a serious, lifelong illness including liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C infection is diagnosed by testing for the presence of HCV antibodies and HCV RNA. Management is supportive but includes direct antiviral agents (DAAs) if infection does not resolve spontaneously.

Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Hepatitis B virus is transmitted by exposure to infectious blood or body fluids. Examples of types of exposure include sexual intercourse, IV drug use, and childbirth. The virus can cause potentially life-threatening liver disease. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Management of acute hepatitis is typically supportive. Administration of antivirals or liver transplantation may be necessary in fulminant and chronic cases.

Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Diagnosis is clinical. Management requires treating the underlying disease, managing complications, and, if required, liver transplantation.

Nonalcoholic fatty liver disease is a spectrum of liver pathology that arises due to accumulation of triglycerides in hepatocytes. Risk factors include diabetes mellitus, insulin resistance, obesity, and hypertension, among others. Nonalcoholic fatty liver disease ranges from fatty liver or hepatic steatosis but can lead to nonalcoholic steatohepatitis (NASH), which features fatty deposits and inflammation. Progressive liver injury and fibrosis irreversibly develop into cirrhosis and, possibly, primary liver cancer. Patients are usually asymptomatic but may present with hepatomegaly and right upper quadrant discomfort. Although liver biopsy is the diagnostic gold standard, the diagnosis can also be established by clinical history, imaging, and laboratory tests. The mainstay of management is lifestyle modifications (weight loss and exercise) with control of associated comorbidities.

Budd-Chiari syndrome is a condition resulting from the interruption of the normal outflow of blood from the liver. The primary type arises from a venous process (affecting the hepatic veins or inferior vena cava) such as thrombosis, but can also be from a lesion compressing or invading the veins (secondary type). The patient typically presents with hepatomegaly, ascites, and abdominal discomfort. Onset is often subacute or chronic. Diagnosis is confirmed by Doppler ultrasound. Treatment involves addressing the underlying condition that caused the venous occlusion. Further management involves prevention of further clotting (anticoagulation), restoration of blood flow, and decompressing the liver. Liver transplantation is considered if initial treatment fails and/or the patient has decompensated liver cirrhosis.

The most common benign liver tumors include hepatic hemangiomas, focal nodular hyperplasia, and hepatic adenomas. These tumors are mostly asymptomatic and/or found incidentally on abdominal imaging. While these tumors are benign, large lesions can cause symptoms such as upper abdominal pain, or produce complications such as bleeding. Malignant potential is a concern for hepatic adenoma, depending on risk factors. The diagnosis is based on imaging studies, with characteristic findings defining the tumor. Biopsy generally is reserved for equivocal cases. Management is observation for most small, asymptomatic, and non-growing tumors. However, high-risk factors, symptoms, increasing tumor size, and complications dictate the need for surgical intervention.

Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Treatment options include resection and chemo-/radiotherapy, and liver transplantation in select cases. Liver metastases are much more common than primary liver cancers and usually originate from colorectal, lung, breast, and pancreatic primary sites. Metastases are most commonly diagnosed by CT or PET scans. Management depends on the type and stage of primary cancer.

The hepatitis E virus (HEV) is a small nonenveloped virus that contains linear, single-stranded, positive-sense RNA, making it similar to norovirus. Transmission of HEV is via the fecal–oral route and is clinically similar to that of hepatitis A. However, unlike hepatitis A, hepatitis E is quite severe, especially in pregnant women, and may cause fulminant hepatitis along with hepatic encephalopathy over a period of approximately 8 weeks. Management is mainly preventive and includes avoiding contaminated drinking water, good sanitation, and adequate personal hygiene.

Nonsteroidal antiinflammatory drugs (NSAIDs) are a class of medications consisting of aspirin, reversible NSAIDs, and selective NSAIDs. NSAIDs are used as antiplatelet, analgesic, antipyretic, and antiinflammatory agents. Common side effects include GI irritation, prolonged bleeding, and AKI.

Alpha-1 antitrypsin deficiency is a genetic disorder caused by inherited genetic mutations of the SERPINA1 gene, causing the defective production of the protease inhibitor alpha-1 antitrypsin (AAT). These mutations can lead to deficiency of the enzyme causing lung disease, production of an abnormal form of the enzyme leading to liver dysfunction, or both. Patients commonly present with emphysema, spontaneous pneumothorax, cirrhosis, hepatitis, or hepatocellular carcinoma. There is no known cure. Management is supportive and includes infusion of AAT, treatment of comorbidities, and liver transplantation. Prognosis may vary based on the form of disease contracted and the severity of symptoms.

The hepatitis A virus (HAV) is a nonenveloped virus of the Picornaviridae family with single-stranded RNA. The virus replicates in the liver, is excreted in the bile, and is found in high concentrations in the stool of acutely infected individuals. The 2 main routes of infection are consumption of contaminated food or water and direct contact with an infected person. HAV causes an acute, highly contagious hepatitis with unspecific prodromal symptoms such as fever and malaise followed by jaundice and elevated liver transaminases. Most individuals recover fully within a few months, and the immunity resulting from HAV infection is lifelong. Unlike hepatitis B and C, HAV infection does not result in chronic infection or chronic liver disease. Preventive vaccination is available for HAV and is recommended for individuals with increased risk of exposure and, in some countries such as the United States, for all children > 12 months of age.

Hepatitis D virus (HDV) is a small enveloped, single-stranded RNA virus. Hepatitis D virus is considered a satellite virus, as it requires the presence of hepatitis B virus (HBV) for assembly and secretion. Therefore, in order for an individual to contract hepatitis D, coinfection or superinfection with HBV is required. Like HBV, HDV is transmitted parenterally, through unprotected sexual intercourse, or perinatally. Clinical presentation is that of a classical viral hepatitis, including coinfection of HDV and HBV, which is considered the most serious form of hepatitis because of the high mortality rate. For acute cases, management is supportive, whereas for chronic cases, pegylated interferon alfa (PEG-IFN-α) is needed.

Alcoholic liver disease is a spectrum of disorders ranging from fatty liver to cirrhosis secondary to chronic alcohol abuse. Excessive and prolonged consumption of alcohol results in impairment of the lipolysis pathway, causing inflammatory changes within the hepatocytes. Patients typically present during the hepatitis stage with jaundice, fever, and abdominal pain. Diagnosis is based on a history of alcohol abuse and confirmed by laboratory derangement with an AST/ALT ratio > 2. Alcoholic liver disease carries a high mortality rate if patients present with severe hepatitis. Management aims at alcohol abstinence for reversal (at certain stages) and addressing contributing factors (such as viral infections or drugs) to minimize damage to the hepatocytes. Approximately 10% of patients regress with alcohol abstinence during the hepatitis stage. Cirrhosis is frequently irreversible.

Drug-induced liver injury (DILI) is the most common cause of acute liver failure (ALF). Hepatotoxic drugs can cause injury to the hepatocytes directly in a predictable dose-dependent way or through idiosyncratic reactions (which may be mediated by immune or non-immune processes). The injury mechanisms can have the following effects: hepatitis, cholestasis, vascular lesions, or overlapping changes. The presentation can be acute or chronic, with severe toxicity manifesting as fulminant liver failure. The diagnosis of DILI requires a thorough history and laboratory tests including liver function tests (LFTs) and drug levels, if available. Management consists of discontinuing the drug, supportive therapy, and monitoring for complications. Acetaminophen, 1 of the most common causes of DILI, has a specific treatment, N-acetylcysteine (NAC).

Hereditary hemochromatosis (HH) is an autosomal recessive disorder most often associated with HFE gene mutations. Patients have increased iron intestinal absorption and iron deposition in several organs, such as the liver, heart, skin, and pancreas. The clinical presentation includes the triad of cirrhosis, diabetes, and skin bronzing. Other findings depend on the organ(s) involved. Diagnosis consists of iron studies, showing transferrin (Tf) and ferritin elevation. Genetic screening is recommended among family members. Imaging and invasive studies are performed depending on the associated complications. Management requires phlebotomy (or iron chelation therapy in some cases) to prevent disease progression. The prognosis is good for patients who are early in the disease and undergoing treatment. The presence of hepatic fibrosis is a poor prognostic factor.

Wilson disease (hepatolenticular degeneration) is an autosomal recessive disorder caused by various mutations in the ATP7B gene, which regulates copper transport within hepatocytes. Dysfunction of this transport mechanism leads to abnormal copper accumulations in the liver, brain, eyes, and other organs, with consequent major and variably expressed hepatic, neurologic, and psychiatric disturbances. Liver involvement may manifest as hepatitis, liver failure, or cirrhosis, while basal ganglia involvement causes the extrapyramidal signs. Most patients are diagnosed between the ages of 5 and 35 years (mean: 13 years). Diagnosis is established if the patient has low plasma ceruloplasmin, corneal deposits of copper (Kayser-Fleischer rings), and elevated copper levels in the urine. However, other tests are often needed since not all patients will have all these findings. The prognosis is good for patients without advanced liver disease and who are treated with the chelating agents penicillamine or trientine. Untreated Wilson disease is ultimately fatal, with patients dying from cirrhosis, acute liver failure, or complications due to progressive neurologic disease.

Autoimmune hepatitis (AIH) is a rare form of chronic liver disease in which the immune system attacks the liver causing inflammation. It predominantly affects women. Clinical presentation ranges from asymptomatic cases to patients that present with symptoms of acute liver failure (jaundice, right upper quadrant pain). Because AIH has a 40% mortality in 6 months without treatment, early diagnosis and treatment are imperative. Diagnosis is established by detecting anti-smooth muscle antibodies and performing a confirmatory liver biopsy. Treatment includes corticosteroids and azathioprine. If treatment is initiated early in the disease course, the prognosis is favorable.