Modern imaging techniques allow the diagnosis to be made more easily and without invasive imaging of the biliary tree. Commonly, the disease is limited to the left lobe of the liver. Images taken by CT scan, X-ray, or MRI show enlarged intrahepatic (in the liver) bile ducts due to ectasia. Using an ultrasound, tubular dilation of the bile ducts can be seen. On a CT scan, Caroli disease can be observed by noting the many fluid-filled, tubular structures extending to the liver. A high-contrast CT must be used to distinguish the difference between stones and widened ducts. Bowel gas and digestive habits make it difficult to obtain a clear sonogram, so a CT scan is a good substitution. When the intrahepatic bile duct wall has protrusions, it is clearly seen as central dots or a linear streak. Caroli disease is commonly diagnosed after this “central dot sign” is detected on a CT scan or ultrasound. However, cholangiography is the best, and final, approach to show the enlarged bile ducts as a result of Caroli disease.

Blood tests should be done, importantly liver-function series, which will give a good impression of the patient's broad metabolic picture.

A complete blood test can help distinguish intrinsic liver disease from extrahepatic bile-duct obstruction. An ultrasound of the liver can reliably detect a dilated biliary-duct system,

it can also detect the characteristics of a cirrhotic liver.Computerized tomography (CT) can help to obtain accurate anatomical information, in individuals with hepatomegaly.

Diagnosis is made by an assessment of symptoms, physical exam, and medical history, in conjunction with blood tests, a liver biopsy, and imaging. Diagnosis is often made following investigation of prolonged jaundice that is resistant to phototherapy and/or exchange transfusions, with abnormalities in liver enzyme tests. Ultrasound or other forms of imaging can confirm the diagnosis. Further testing may include radioactive scans of the liver and a liver biopsy.

The differential diagnoses are extensive and include: Alagille syndrome, alpha-1-antitrypsin deficiency, Byler disease (progressive familial intrahepatic cholestasis), Caroli disease, choledochal cyst, cholestasis, congenital cytomegalovirus disease, congenital herpes simplex virus infection, congenital rubella, congenital syphilis, congenital toxoplasmosis, cystic fibrosis, galactosemia, idiopathic neonatal hepatitis, lipid storage disorders, neonatal hemochromatosis, and total parenteral nutrition-associated cholestasis.

Mortality is indirect and caused by complications. After cholangitis occurs, patients typically die within 5–10 years.

At CT scans, bile duct hamartomas appear as small, well-defined hypo- or isoattenuating masses with little or no enhancement after contrast administration. At MRI, they appear hypointense on T1-weighted images, iso- or slightly hyperintense on T2-weighted images, and hypointense after administration of gadolinium based contrast-agent. On imaging, multiple hamartomas may look similar to metastases or microabscesses.

Imaging by ultrasonography, MRCP, or CT scan usually make the diagnosis. MRCP can be used to define the lesion anatomically prior to surgery.

Occasionally Mirizzi's syndrome is diagnosed or confirmed on ERCP when requested to alleviate obstructive jaundice or cholangitis by means of an endoscopically placed stent, or when USS has been wrongly reported as choledocolithiasis.

Treatment of hepatomegaly will vary depending on the cause of the liver enlargement and hence accurate diagnosis is the primary concern. In the case of auto-immune liver disease, prednisone and azathioprine may be used for treatment.

In the case of lymphoma the treatment options include single-agent (or multi-agent) chemotherapy and regional radiotherapy, also surgery may be an option in specific situations.Meningococcal group C conjugate vaccine are also used in some cases.

In primary biliary cirrhosis ursodeoxycholic acid helps the bloodstream remove bile which may increase survival in some affected individuals.

Biochemical markers include a normal GGT for PFIC-1 and -2, with a markedly elevated GGT for PFIC-3. Serum bile acid levels are grossly elevated. Serum cholesterol levels are typically not elevated, as is seen usually in cholestasis, as the pathology is due to a transporter as opposed to an anatomical problem with biliary cells.

Alagille syndrome can be determined by a special kind of newborn screening wherein DNA samples are analyzed for markers in the JAG1 section. The DNA sequence patterns of a child will be analyzed for probabilistic deletions and therefore takes weeks to complete. After detection, the child should be treated with vitamins and necessary diet to develop the liver function postnatally.

Computed tomography (CT) findings in AIP include a "diffusely enlarged hypodense" pancreas or a focal mass that may be mistaken for a pancreatic malignancy. A low-density, "capsule-like rim on CT" (possibly corresponding to an inflammatory process involving peripancreatic tissues) is thought to be an additional characteristic feature (thus the mnemonic: "sausage-shaped"). Magnetic resonance imaging (MRI) reveals a diffusely decreased signal intensity and delayed enhancement on dynamic scanning. The characteristic ERCP finding is segmental or diffuse irregular narrowing of the main pancreatic duct, usually accompanied by an extrinsic-appearing stricture of the distal bile duct. Changes in the extrapancreatic bile duct similar to those of primary sclerosing cholangitis (PSC) have been reported.

The role of endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration (EUS-FNA) in the diagnosis of AIP is not well described, and EUS findings have been described in only a small number of patients. In one study, EUS revealed a diffusely swollen and hypoechoic pancreas in 8 of the 14 (57%) patients, and a solitary, focal, irregular mass was observed in 6 (46%) patients. Whereas EUS-FNA is sensitive and specific for the diagnosis of pancreatic malignancy, its role in the diagnosis of AIP remains unclear.

A bile duct hamartoma or biliary hamartoma, is a benign tumour-like malformation

of the liver.

They are classically associated with polycystic liver disease, as may be seen in the context of polycystic kidney disease, and represent a malformation of the liver plate.

The disease is typically progressive, leading to fulminant liver failure and death in childhood, in the absence of liver transplantation. Hepatocellular carcinoma may develop in PFIC-2 at a very early age; even toddlers have been affected.

Ultrasonography of liver tumors involves two stages: detection and characterization. Tumor detection is based on the performance of the method and should include morphometric information (three axes dimensions, volume) and topographic information (number, location specifying liver segment and lobe/lobes). The specification of these data is important for staging liver tumors and prognosis. Tumor characterization is a complex process based on a sum of criteria leading towards tumor nature definition. Often, other diagnostic procedures, especially interventional ones are no longer necessary. Tumor characterization using the ultrasound method will be based on the following elements: consistency (solid, liquid, mixed), echogenicity, structure appearance (homogeneous or heterogeneous), delineation from adjacent liver parenchyma (capsular, imprecise), elasticity, posterior acoustic enhancement effect, the relation with neighboring organs or structures (displacement, invasion), vasculature (presence and characteristics on Doppler ultrasonography and contrast-enhanced ultrasound (CEUS).

The most common method of testing for hepatoblastoma is a blood test checking the alpha-fetoprotein level. Alpha-fetoprotein (AFP) is used as a biomarker to help determine the presence of liver cancer in children. At birth, infants have relatively high levels of AFP, which fall to normal adult levels by the first year of life. The normal level for AFP in children has been reported as lower than 50 nanograms per milliliter (ng/ml) and 10 ng/ml. An AFP level greater than 500 (ng/ml) is a significant indicator of hepatoblastoma. AFP is also used as an indicator of treatment success. If treatments are successful in removing the cancer, the AFP level is expected to return to normal.

Intraductal papillary mucinous neoplasms can come to clinical attention in a variety of different ways. The most common symptoms include abdominal pain, nausea and vomiting. The most common signs patients have when they come to medical attention include jaundice (a yellowing of the skin and eyes caused by obstruction of the bile duct), weight loss, and acute pancreatitis. These signs and symptoms are not specific for an intraductal papillary mucinous neoplasm, making it more difficult to establish a diagnosis. Doctors will therefore often order additional tests.

Once a doctor has reason to believe that a patient may have an intraductal papillary mucinous neoplasm, he or she can confirm that suspicion using one of a number of imaging techniques. These include computerized tomography (CT), endoscopic ultrasound (EUS), and magnetic resonance cholangiopancreatography (MRCP). These tests will reveal dilatation of the pancreatic duct or one of the branches of the pancreatic duct. In some cases a fine needle aspiration (FNA) biopsy can be obtained to confirm the diagnosis. Fine needle aspiration biopsy can be performed through an endoscope at the time of endoscopic ultrasound, or it can be performed through the skin using a needle guided by ultrasound or CT scanning.

IPMN forms cysts (small cavities or spaces) in the pancreas. These cysts are visible in CT scans (X-ray computed tomography). However, many pancreatic cysts are benign (see Pancreatic disease).

A growing number of patients are now being diagnosed before they develop symptoms (asymptomatic patients). In these cases, the lesion in the pancreas is discovered accidentally (by chance) when the patient is being scanned (i.e. undergoing an ultrasound, CT or MRI scan) for another reason. Up to 6% of patients undergoing pancreatic resection did so for treatment of incidental IPMNs.

In 2011, scientists at Johns Hopkins reported that they have developed a gene-based test that can be used to distinguish harmless from precancerous pancreatic cysts. The test may eventually help patients with harmless cysts avoid needless surgery. Bert Vogelstein and his colleagues discovered that almost all of the precancerous cysts (intraductal papillary mucinous neoplasms) of the pancreas have mutations in the KRAS and/or the GNAS gene. The researchers then tested a total of 132 intraductal papillary mucinous neoplasms for mutations in KRAS and GNAS. Nearly all (127) had mutations in GNAS, KRAS or both. Next, the investigators tested harmless cysts such as serous cystadenomas, and the harmless cysts did not have GNAS or KRAS mutations. Larger numbers of patients must be studied before the gene-based test can be widely offered.

Serous cystic neoplasms can come to clinical attention in a variety of ways. The most common symptoms are very non-specific and include abdominal pain, nausea and vomiting. In contrast to many of the other tumors of the pancreas, patients rarely develop jaundice (a yellowing of the skin and eyes caused by obstruction of the bile duct), or weight loss. These signs and symptoms are not specific for a serous cystic neoplasm, making it more difficult to establish a diagnosis. Doctors will therefore often order additional tests.

Once a doctor has reason to believe that a patient may have serous cystic neoplasm, he or she can confirm that suspicion using one of a number of imaging techniques. These include computerized tomography (CT), endoscopic ultrasound (EUS), and magnetic resonance cholangiopancreatography (MRCP). These tests will reveal a cystic mass within the pancreas. The cysts do not communicate with the larger pancreatic ducts. In some cases a fine needle aspiration (FNA) biopsy can be obtained to confirm the diagnosis. Fine needle aspiration biopsy can be performed through an endoscope at the time of endoscopic ultrasound, or it can be performed through the skin using a needle guided by ultrasound or CT scanning.

A growing number of patients are now being diagnosed before they develop symptoms (asymptomatic patients). In these cases, the lesion in the pancreas is discovered accidentally (by chance) when the patient is being scanned (x-rayed) for another reason.

Most recently the fourteenth Congress of the International Association of Pancreatology developed the International Consensus Diagnostic Criteria (ICDC) for AIP. The ICDC emphasizes five cardinal features of AIP which includes the imaging appearance of pancreatic parenchyma and the pancreatic duct, serum IgG4 level, other organ involvement with IgG4-related disease, pancreatic histology and response to steroid therapy.

In 2002, the Japanese Pancreas Society proposed the following diagnostic criteria for autoimmune pancreatitis:

For diagnosis, criterion I (pancreatic imaging) must be present with criterion II (laboratory data) and/or III (histopathologic findings).

Mayo Clinic has come up with five diagnostic criteria called HISORt criteria which stands for histology, imaging, serology, other organ involvement, and response to steroid therapy.

Upon discovery of a liver tumor, the main issue in the workup is to determine whether the tumor is benign or malignant. Many imaging modalities are used to aid in the diagnosis of malignant liver tumors. For the most common of these, hepatocellular carcinoma (HCC), these include sonography (ultrasound), computed tomography (CT) and magnetic resonance imaging (MRI). When imaging the liver with ultrasound, a mass greater than 2 cm has more than 95% chance of being HCC. The majority of cholangiocarcimas occur in the hilar region of the liver, and often present as bile duct obstruction. If the cause of obstruction is suspected to be malignant, endoscopic retrograde cholangiopancreatography (ERCP), ultrasound, CT, MRI and magnetic resonance cholangiopancreatography (MRCP) are used.

Tumor markers, chemicals sometimes found in the blood of people with cancer, can be helpful in diagnosing and monitoring the course of liver cancers. High levels of alpha-fetoprotein (AFP) in the blood can be found in many cases of HCC and intrahepatic cholangiocarcinoma. Cholangiocarcinoma can be detected with these commonly used tumor markers: carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA) and cancer antigen 125 (CA125). These tumour markers are found in primary liver cancers, as well as in other cancers and certain other disorders..

Diagnosis is typically confirmed by ultrasound. Complications may be detected on blood tests.

A positive Murphy's sign is a common finding on physical examination during a gallbladder attack.

Cholestasis can be suspected when there is an elevation of both 5'-nucleotidase and ALP enzymes. With a few exceptions, the optimal test for cholestasis would be elevations of serum bile acid levels. However, this is not normally available in most clinical settings. The gamma-glutamyl transferase (GGT) enzyme was previously thought to be helpful in confirming a hepatic source of ALP; however, GGT elevations lack the necessary specificity to be a useful confirmatory test for ALP. Normally GGT and ALP are anchored to membranes of hepatocytes and are released in small amounts in hepatocellular damage. In cholestasis, synthesis of these enzymes is induced and they are made soluble. GGT is elevated because it leaks out from the bile duct cells due to pressure from inside bile ducts.

In a later stage of cholestasis AST, ALT and bilirubin may be elevated due to liver damage as a secondary effect of cholestasis.

Because of their location, these tumors tend to become symptomatic late in their development and therefore are not usually resectable at the time of presentation. This is variable as, due to obstruction, jaundice may present early and compel the patient to seek help. Complete resection of the tumor offers hope of long-term survival, and of late there has been renewed interest in liver transplantation from deceased donors along with add on therapy. Prognosis remains poor.

Simple cholecystectomy is suitable for type I patients. For types II–IV, subtotal cholecystectomy can be performed to avoid damage to the main bile ducts. Cholecystectomy and bilioenteric anastomosis may be required. Roux-en-Y hepaticojejunostomy has shown good outcome in some studies.

PSC is generally diagnosed on the basis of having at least two of three clinical criteria after secondary causes of sclerosing cholangitis have been ruled out:

- serum alkaline phosphatase (ALP) > 1.5x the upper limit of normal for longer than 6 months;

- cholangiography demonstrating biliary strictures or irregularity consistent with PSC; and,

- liver biopsy consistent with PSC (if available).

Historically, a cholangiogram would be obtained via endoscopic retrograde cholangiopancreatography (ERCP), which typically reveals "beading" (alternating strictures and dilation) of the bile ducts inside and/or outside the liver. Currently, the preferred option for diagnostic cholangiography, given its non-invasive yet highly accurate nature, is magnetic resonance cholangiopancreatography (MRCP), a magnetic resonance imaging technique. MRCP has unique strengths, including high spatial resolution, and can even be used to visualize the biliary tract of small animal models of PSC.

Most people with PSC have evidence of autoantibodies and abnormal immunoglobulin levels. For example, approximately 80% of people with PSC have perinuclear anti-neutrophil cytoplasmic antibodies; however, this and other immunoglobulin findings are not specific to those with PSC and are of unclear clinical significance/consequence. Antinuclear antibodies and anti-smooth muscle antibody are found in 20%-50% of PSC patients and, likewise, are not specific for the disease but may identify a subgroup of PSC patients who also have autoimmune hepatitis (i.e. PSC-AIH overlap syndrome).

Other markers which may be measured and monitored are a complete blood count, serum liver enzymes, bilirubin levels (usually grossly elevated), kidney function, and electrolytes. Fecal fat measurement is occasionally ordered when symptoms of malabsorption (e.g., gross steatorrhea) are prominent.

The differential diagnosis can include primary biliary cholangitis (formerly referred to as primary biliary cirrhosis), drug-induced cholestasis, cholangiocarcinoma, IgG4-related disease, post-liver transplantation non-anastomotic biliary strictures, and HIV-associated cholangiopathy. Primary sclerosing cholangitis and primary biliary cholangitis are distinct entities and exhibit important differences, including the site of tissue damage within the liver, associations with inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, response to treatment, and risks of disease progression.

Choledochal cysts are treated by surgical excision of the cyst with the formation of a roux-en-Y anastomosis hepaticojujenostomy/ choledochojujenostomy to the biliary duct.

Future complications include cholangitis and a 2% risk of malignancy, which may develop in any part of the biliary tree. A recent article published in Journal of Surgery suggested that choledochal cysts could also be treated with single-incision laparoscopic hepaticojejunostomy with comparable results and less scarring. In cases of saccular type of cyst, excision and placement of T-shaped tube is done.

Currently, there is no accepted indication for fetal intervention in the management of prenatally suspected choledochal cysts.